Novel inhibitor compounds of phosphodiesterase type 10a

ABSTRACT

The present invention relates to compounds which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders. 
     
       
         
         
             
             
         
       
         
         
           
             wherein 
             X 1  is CH or N, X 2  is C—R 5  or N, Y is O or S, 
             R 1  is inter alia C 2 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 8 -cycloalkyl, C 5 -C 8 -cycloalkyl carrying a fused benzene ring, or a moiety Z 1 —Ar 1 ; 
             R 2  is a radical of the formula CR 21 R 22 R 23  or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents R a , 
             R 3  is inter alia hydrogen, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 8 -cycloalkyl, etc, or 
             R 2  and R 3  together with the nitrogen atom, to which they are bound form an optionally substituted saturated 5- to 7-membered heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO 2 ; 
             R 4  is inter alia C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl or Z 4 —Ar 4 ; 
             R 5  is inter alia hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkoxy, —Z 5 —Ar 5 , —O—Z 5 —Ar 5 , etc; 
             where Z 1  to Z 5 , Ar 1  to Ar 5 , R a , R 21 , R 22 , and R 23  are as defined in the claims.

CROSS-REFERENCE TO RELATED APPLICATION

This claims priority to U.S. Provisional Patent Application No.61/557,878, filed on Nov. 9, 2011, the contents of which are hereinfully incorporated by reference.

The present invention relates to compounds which are inhibitors ofphosphodiesterase type 10A and to their use for the manufacture of amedicament and which thus are suitable for treating or controlling ofmedical disorders selected from neurological disorders and psychiatricdisorders, for ameliorating the symptoms associated with such disordersand for reducing the risk of such disorders.

BACKGROUND OF THE INVENTION

Phosphodiesterase type 10A (hereinafter PDE10A) is a dual-substratephosphodiesterase that can convert both cAMP to AMP and cGMP to GMP.PDE10A is highly prominent in the mammalian brain. In the rat, as wellas in other mammalian species, PDE10A and the mRNA of PDE10A are highlyenriched in the GABAergic medium spiny projection neurons (MSNs) of thestriatal complex (caudate nucleus, nucleus accumbens, and olfactorytubercle) where the output is regulated by the effect of PDE10A on cAMPand cGMP signalling cascades (see e.g. C. J. Schmidt et al, The Journalof Pharmacology and Experimental Therapeutics 325 (2008) 681-690, A.Nishi, The Journal of Neuroscience 2008, 28, 10450-10471).

MSNs express two functional classes of neurons: the D₁ class expressingD₁ dopamine receptors and the D₂ class expressing D₂ dopamine receptors.The D₁ class of neurons is part of the ‘direct’ striatal output pathway,which broadly functions to facilitate behavioral responses. The D₂ classof neurons is part of the ‘indirect’ striatal output pathway, whichfunctions to suppress behavioral responses that compete with those beingfacilitated by the ‘direct’ pathway. PDE10A regulation of cAMP and/orcGMP signaling in the dendritic compartment of these neurons may beinvolved in filtering the cortico/thalamic input into the MSN.Furthermore, PDE10A may be involved in the regulation of GABA release inthe substantia nigra and globus pallidus (Seeger, T. F. et al. BrainResearch, 2003, 985, 1 13-126). Inhibition of PDE10A results in striatalactivation and behavioral suppression such as dampened locomotion,inhibition of conditioned avoidance response (CAR), and activity in therat auditory gating model, suggesting that inhibitors ofphosphodiesterase type 10A represent a novel class of antipsychoticagents.

The hypotheses around the physiological role of PDE10A and thetherapeutic utility of PDE10A inhibitors derive in part from studieswith papaverine (J. A. Siuciak et al. loc. cit.), the first extensivelyprofiled pharmacological tool compound for this target. The PDE10Ainhibitor papaverine was shown to be active in several antipsychoticmodels. Papaverine potentiated the cataleptic effect of the D₂ receptorantagonist haloperidol in rats, but did not cause catalepsy on its own(WO 03/093499). Papaverine reduced hyperactivity in rats induced by PCP,while reduction of amphetamine-induced hyperactivity was insignificant(WO 03/093499). These models suggest that PDE10A inhibition has theclassic antipsychotic potential that would be expected from theoreticalconsiderations. Papaverine, however has significant limitations in thisregard with relatively poor potency and selectivity and a very shortexposure half-life after systemic administration. It was found thatinhibition of PDE10A reverses subchronic PCP-induced deficits inattentional set-shifting in rats suggesting that PDE10A inhibitors mightalleviate cognitive deficits associated with schizophrenia. (Rodefer etal., Eur. J. Neurosci., 4 (2005) 1070-1076).

The discovery of a new class of PDE10A inhibitors with improved potency,selectivity, and pharmacokinetic properties, provided an opportunity tofurther explore the physiology of PDE10A and the potential therapeuticutility of inhibiting this enzyme. The new class of inhibitors areexemplified by MP-10 (PF-2545920:2-{4-[1-methylpyridine-4-yl-1-H-pyrazol-3-31y]phenoxymethyl}-quinoline)and TP-10, i.e.2-{4-[pyridine-4-yl-1-(2,2,2-trifluoroethyl)-1-H-pyrazol-3-31y]phenoxymethyl}-quinoline.The compounds offer a therapeutic approach to the treatment ofschizophrenia (see C. J. Schmidt et al., loc cit.; S. M. Grauer et al.,Journal of Pharmacology and Experimental Therapeutics, fast forward DOI10.1124 JPET 109.155994). Positive signals in rodent models ofschizophrenia include the: attenuation of conditioned avoidance response(CAR), inhibition of hyperactivity caused by amphetamine-induceddopamine release or phencyclidine (PCP) mediated NMDA receptor blockade,attenuation of pharmacologically impaired social or object recognition,and antagonism of apomorphine-induced climbing. Taken together, thesedata suggest a broad suppression of all 3 symptoms clusters (positivesymptoms, negative symptoms & cognitive dysfunctions) linked toschizophrenia (see C. J. Schmidt et al., loc cit.; S. M. Grauer et al.,loc. cit).

Beyond schizophrenia, selective PDE10 inhibitiors may have the potentialfor the treatment of Huntington's disease (S. H. Francis et al.,Physiol. Rev., 91 (2011) 651-690) and they may be an therapeutic optionfor substance abuse disorders (F. Sotty et al., J. Neurochem., 109(2009) 766-775). Furthermore, it has been suggested that PDE10Ainhibitors may be useful for treatment of obesity and non-insulindependent diabetes (see e.g. WO 2005/120514, WO 2005/012485, Cantin etal, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873).

In summary, inhibitors of PDE10A offer a promising therapeutic approachto the treatment or prevention of neurological and psychiatricdisorders, in particular schizophrenia and related disorders, includingsymptoms linked to schizophrenia such as cognitive dysfunction.

Several classes of compounds which are inhibitors of PDE10A have beendescribed in the art, the recent compound groups are:

Pyrido[3,2-e]pyridazines—see WO 2007/137819, WO 2007/137820, WO2009/068246, WO 2009/068320, WO 2009/070583 and WO 2009/070584;

4-substituted phthalazines and quinazolines WO 2007/085954, WO2007/022280, WO 2007/096743, WO 2007/103370, WO 2008/020302, WO2008/006372 and WO 2009/036766;

4-substituted cinnazolines—see WO 2006/028957, WO 2007/098169, WO2007/098214, WO 2007/103554, WO 2009/025823 and WO 2009/025839;

Isoquinolines and isoquinolinones—see WO 2007/100880 and WO 2009/029214;

MP10 and MP10 like compounds: US 2007/0155779, WO 2008/001182 and WO2008/004117; and

Benzodiazepines—see WO 2007/082546.

For a further review see also T. Chappie et al. Current Opinion in DrugDiscovery & Development 12(4), (2009) 458-467) and the literature citedtherein.

Although some of the compounds of prior art are known to inhibit PDE10Aeffectively having IC₅₀ values of less than 50 nM, there is still anongoing need for compounds which inhibit PDE10A. In particular, there isan ongoing need for compounds which have one of the followingcharacteristics:

-   -   i. Selective inhibition of PDE10A, in particular vis-à-vis        inhibition of other phosphodisesterases such as PDE3 or PDE4;    -   ii. metabolic stability, in particular microsomal stability,        e.g. measured in vitro, in liver microsomes from various species        (e.g. rat or human) in human cells, such as hepatocytes;    -   iii. no or only low inhibition of cytochrome P450 (CYP) enzymes:        cytochrome P450 (CYP) is the name for a superfamily of heme        proteins having enzymatic activity (oxidase). They are also        particularly important for the degradation (metabolism) of        foreign substances such as drugs or xenobiotics in mammalian        organisms. The principal representatives of the types and        subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6        and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice,        cimetidine, erythromycin) are used at the same time as medicinal        substances which are degraded by this enzyme system and thus        compete for the same binding site on the enzyme, the degradation        thereof may be slowed down and thus effects and side effects of        the administered medicinal substance may be undesirably        enhanced;    -   iv. a suitable solubility in water (in mg/ml);    -   v. suitable pharmacokinetics (time course of the concentration        of the compound of the invention in plasma or in tissue, for        example brain). The pharmacokinetics can be described by the        following parameters: half-life, volume of distribution (in        l·kg⁻¹), plasma clearance (in l·h⁻¹·kg⁻¹), AUC (area under the        curve, area under the concentration-time curve (in ng·h·l⁻¹),        oral bioavailability, (the dose-normalized ratio of AUC after        oral administration and AUC after intravenous administration),        the so-called brain-plasma ratio (the ratio of AUC in brain        tissue and AUC in plasma);    -   vi. no or only low blockade of the hERG channel: compounds which        block the hERG channel may cause a prolongation of the QT        interval and thus lead to serious disturbances of cardiac rhythm        (for example so-called “torsade de pointes”). The potential of        compounds to block the hERG channel can be determined by means        of the displacement assay with radiolabelled dofetilide which is        described in the literature (G. J. Diaz et al., Journal of        Pharmacological and Toxicological Methods, 50 (2004), 187-199).        A smaller IC50 in this dofetilide assay means a greater        probability of potent hERG blockade. In addition, the blockade        of the hERG channel can be measured by electrophysiological        experiments on cells which have been transfected with the hERG        channel, by so-called whole-cell patch clamping (G. J. Diaz et        al., Journal of Pharmacological and Toxicological Methods, 50        (2004), 187-199).    -   vii. high free fraction in brain, i.e. the fraction of the        compound bound to proteins should be low.    -   viii. low lipophilicity.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is thus based on the object of providing compoundswhich inhibit PDE10A at low concentrations.

The compounds are further intended to display at least one of theproperties i. to viii. mentioned above, in particular high selectivitywith regard to inhibition of PDE10A, high selectivity vis-à-vis otherphosphodiesterases such as, enhanced metabolic stability, in particularmicrosomal and/or cytosolic stability, low affinity to the HERGreceptor, low inhibition of cytochrome P450 (CYP) enzymes, suitablesolubility in water and suitable pharmacokinetics.

This object and further objects are achieved by the compounds of thegeneral formula I described below, the N-oxides, the prodrugs, thehydrates and the tautomers thereof and the pharmaceutically suitablesalts thereof:

wherein

-   -   X¹ is CH or N,    -   X² is C—R⁵ or N,    -   Y is O or S,    -   R¹ is selected from the group consisting of C₂-C₈-alkyl,        C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,        C₅-C₈-cycloalkyl carrying a fused benzene ring, fluorinated        C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinated        C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)) and a moiety        Z¹—Ar¹;    -   R² is a radical of the formula CR²¹R²²R²³ or phenyl or 5- or        6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members        which are selected from O, S and N, where phenyl and monocyclic        hetaryl are unsubstituted or may carry 1, 2 or 3 identical or        different substituents R^(a), where        -   R²¹ is selected from the group consisting of hydrogen,            C₁-C₈-alkyl, trimethylsilyl, C₂-C₈-alkenyl,            C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl, fluorinated            C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinated            C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,            hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)),            (CH₂)_(m)C(O)O—R^(d), (CH₂)_(m)C(O)N(R^(e))(R^(f)) and            Z²—Ar²,        -   R²² is selected from the group consisting of hydrogen,            fluorine, C₁-C₈-alkyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl,            C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,            C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinated            C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,            hydroxy-C₁-C₄-alkyl and C₁-C₄-alkyl-N(R^(b))(R^(c)), or        -   R²¹ and R²² together with the carbon atom, to which they are            bound form a saturated 5- to 7-membered carbocyclic ring or            a saturated 5- to 7-membered heterocyclic ring which has 1,            2 or 3 heteroatoms or heteroatom containing groups selected            from the group of O, N, S, SO and SO₂ as ring members, where            the carbocyclic ring and the heterocyclic ring may be            unsubstituted or may be substituted by 1, 2 or 3 identical            or different substituents R^(g), and where the carbocyclic            ring and the heterocyclic ring may carry a fused benzene            ring or a fused 5- or 6-membered heteroaromatic ring, where            the fused rings themselves are unsubstituted or carry 1, 2            or 3 substituents R^(h),        -   R²³ is selected from the group consisting of hydrogen,            fluorine, C₁-C₈-alkyl and C₁-C₄-fluoroalkyl;    -   R³ is selected from the group consisting of hydrogen,        C₁-C₈-alkyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,        C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)), and        trimethylsilyl, or    -   R² and R³ together with the nitrogen atom, to which they are        bound form a saturated 5- to 7-membered heterocyclic ring which,        in addition to the nitrogen atom, may have 1 or 2 further        heteroatoms or heteroatom containing groups selected from the        group of O, N, S, SO and SO₂ as ring members, where the        heterocyclic ring may be unsubstituted or may be substituted by        1, 2 or 3 identical or different substituents R³¹, and where the        heterocyclic ring may carry a fused benzene ring or a fused 5-        or 6-membered heteroaromatic ring, where the fused rings        themselves are unsubstituted or carry 1, 2 or 3 substituents        R³², where        -   R³¹ is selected from the group consisting of halogen, CN,            OH, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy,            fluorinated C₁-C₄-alkoxy, N(R^(b))(R^(c)), C(O)O—R^(d),            C(O)N(R^(e))(R^(f)), where one radical R³¹ may also be a            moiety Z³—Ar³,        -   R³² is selected from the group consisting of halogen, CN,            OH, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy,            fluorinated C₁-C₄-alkoxy, N(R^(b))(R^(c)), C(O)O—R^(d) and            C(O)N(R^(e))(R^(f));    -   R⁴ is selected from the group consisting of C₁-C₄-alkyl,        C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₄-alkyl and Z⁴—Ar⁴,    -   R⁵ is selected from the group consisting of hydrogen, halogen,        C₁-C₄-alkyl, C₁-C₄-fluoroalkyl, C₁-C₄-alkoxy,        C₁-C₄-fluoroalkoxy, —Z⁵—Ar⁵, —O—Z⁵—Ar⁵, C₃-C₆-cycloalkyl,        C₃-C₆-cycloalkyl-C₁-C₄-alkyl, C₃-C₆-cycloalkoxy and        C₃-C₆-cycloalkyl-C₁-C₄-alkoxy, where the cyclic radical in the        last four mentioned groups may be unsubstituted, partially or        completely fluorinated or carries 1, 2, 3 or 4 methyl groups;        -   Ar¹ is selected from the group consisting of phenyl,            monocyclic 5- or 6-membered hetaryl or bicyclic 9- or            10-membered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms            as ring members which are selected from O, S and N, where            phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3            identical or different substituents R^(h);        -   Ar² is phenyl or monocyclic 5- or 6-membered hetaryl having            1, 2 or 3 heteroatoms as ring members which are selected            from O, S and N, where phenyl and monocyclic hetaryl are            unsubstituted or may carry 1, 2 or 3 identical or different            substituents R^(h);        -   Ar³ is phenyl or monocyclic 5- or 6-membered hetaryl having            1, 2 or 3 heteroatoms as ring members which are selected            from O, S and N, where phenyl and monocyclic hetaryl are            unsubstituted or may carry 1, 2 or 3 identical or different            substituents R^(h);        -   Ar⁴ and Ar⁵ are independently of each other selected from            the group consisting of phenyl and monocyclic 5- or            6-membered hetaryl having 1, 2 or 3 heteroatoms as ring            members which are selected from O, S and N, where phenyl and            monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3            identical or different substituents R^(k);        -   Z¹, Z⁴, Z⁵ are independently of each other C₁-C₄-alkylene;        -   Z² is a single bond or C₁-C₄-alkylene;        -   Z³ is a single bond, C₁-C₄-alkylene, O, N, S, SO or SO₂;        -   R^(a) is selected from the group consisting of halogen, CN,            OH, NO₂, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy,            fluorinated C₁-C₄-alkoxy, (CH₂)_(m)N(R^(b))(R^(c)),            C(O)O—R^(d), C(O)N(R^(e))(R^(f)), N(R^(ee))S(O)₂(R^(ff)) and            S(O)₂N(R^(e))(R^(f));        -   R^(b), R^(c), independently of each other are selected from            the group consisting of hydrogen, C₁-C₄-alkyl,            C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl            and benzyl or R^(b) and R^(c) form together with the N atom            to which they are attached a 3- to 7-membered, nitrogen            heterocycle which may have 1, 2 or 3 further different or            identical heteroatoms or heteroatom containing groups            selected from the group of O, N, S, SO and SO₂ as ring            members and which may carry 1, 2, 3, 4, 5 or 6 substituents            selected from C₁-C₄-alkyl;        -   R^(d) is selected from the group consisting of C₁-C₄-alkyl,            C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl            and benzyl;        -   R^(e), R^(f), independently of each other are selected from            the group consisting of hydrogen, C₁-C₄-alkyl,            C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl            and benzyl or R^(e) and R^(f) form together with the N atom            to which they are attached a 3- to 7-membered, nitrogen            heterocycle which may have 1, 2 or 3 further different or            identical heteroatoms or heteroatom containing groups            selected from the group of O, N, S, SO and SO₂ as ring            members and which may carry 1, 2, 3, 4, 5 or 6 substituents            selected from C₁-C₄-alkyl;        -   R^(g) is selected from the group consisting of halogen, CN,            OH, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₄-fluoroalkyl,            C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,            C₃-C₆-cycloalkyl-C₁-C₄-alkyl, fluorinated            C₃-C₆-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,            hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)),            C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy, one R^(g) together            with a carbon atom to which R^(g) is attached may also form            a carbonyl group, one R^(g) may also be phenyl or benzyl,            where the phenyl ring in the last 2 mentioned radicals is            unsubstituted or carries 1, 2 or 3 radicals R^(h);        -   R^(h) is selected from the group consisting of halogen, CN,            OH, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₆-alkoxy,            fluorinated C₁-C₄-alkoxy, C₁-C₄-alkylsulfanyl,            C₁-C₄-alkoxy-C₁-C₄-alkoxy, C₃-C₆-cycloalkyl, fluorinated            C₃-C₆-cycloalkyl, C₃-C₆-cycloalkoxy,            C₃-C₆-cycloalkyl-C₁-C₄-alkoxy, phenoxy, N(R^(b))(R^(c)),            C₁-C₄-alkyl-N(R^(b))(R^(c)), C(O)O—R^(d),            C(O)N(R^(e))(R^(f)), N(R^(ee))S(O)₂(R^(ff)),            S(O)₂N(R^(e))(R^(f)), 3- to 7-membered heterocyclyloxy, 3-            to 7-membered heterocyclyl-C₁-C₄-alkoxy, where heterocyclyl            in the two last mentioned radicals has 1, 2 or 3 heteroatoms            as ring members which are selected from O, S and N, and 5-            to 6-membered hetaryl-C₁-C₄-alkoxy, where hetaryl has 1, 2            or 3 heteroatoms as ring members which are selected from O,            S and N;        -   R^(k) is selected from the group consisting of halogen, CN,            OH, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy,            fluorinated C₁-C₄-alkoxy, N(R^(b))(R^(c)), C(O)O—R^(d),            C(O)N(R^(e))(R^(f)), N(R^(ee))S(O)₂(R^(ff)) and            S(O)₂N(R^(e))(R^(f)) or two radicals R^(k) that are bound to            adjacent carbon atoms together with said carbon atoms may            form fused benzene ring or a fused 5- or 6-membered            heteroaromatic ring having 1 or 2 ring members selected from            O, N and S, where the fused benzene ring and the fused            heteroaromatic ring are unsubstituted or may carry 1, 2 or 3            radicals R^(h);        -   R^(ee) is selected from the group consisting of hydrogen,            C₁-C₄-alkyl, C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl,            C₃-C₆-cycloalkylmethyl and benzyl;        -   R^(ff) is selected from the group consisting of C₁-C₄-alkyl,            C₁-C₄-fluoroalkyl and phenyl, which is unsubstituted or            carries 1, 2 or 3 radicals R^(h);        -   m is 0, 1, 2, 3 or 4.

The present invention therefore relates to the compounds of the generalformula I, the N-oxides, the tautomers and the hydrates thereof, thepharmaceutically acceptable salts of the compounds of formula I, theprodrugs of the compounds of formula I and the pharmaceuticallyacceptable salts of said N-oxides, prodrugs, tautomers or hydrates ofthe compounds of formula I.

The present invention also relates to the compounds of the generalformula I, the N-oxides, the tautomers and the hydrates thereof, thepharmaceutically acceptable salts of the compounds of formula I, theprodrugs of the compounds of formula I and the pharmaceuticallyacceptable salts of said N-oxides, prodrugs, tautomers or hydrates ofthe compounds of formula I for the use in the treatment of a medicaldisorder, selected from neurological and psychiatric disorders which canbe treated by modulation of phosphodiesterase type 10.

The compounds of the formula I, their pharmaceutically acceptable salts,their N-oxides, their prodrugs, their hydrates and their tautomers andthe pharmaceutically acceptable salts of said N-oxides, prodrugs,tautomers or hydrates effectively inhibit PDE10A even at lowconcentrations. They are additionally distinguished by a highselectivity in relation to the inhibition of the PDE10A vis-à-visinhibition of other phosphodiesterease, such as PDE3 or PDE4. Thecompounds of the invention may additionally have one or more of theproperties ii. to viii. mentioned above.

The compounds of the formula I, their pharmaceutically acceptable salts,their N-oxides, their prodrugs, their hydrates and their tautomers andthe pharmaceutically acceptable salts of said N-oxides, prodrugs,tautomers or hydrates are therefore particularly suitable for treatingdisorders and conditions in creatures, especially human creatures, whichcan be treated or controlled by inhibition of phosphodiesterase type10A.

The invention therefore also relates to the use of the compounds of theformula I, their N-oxides, their tautomers, their hydrates and theirpharmaceutically acceptable salts and the pharmaceutically acceptablesalts of said N-oxides, prodrugs, tautomers or hydrates for themanufacture of a medicament, in particular of a medicament which issuitable for the treatment of a disorder or a condition which can betreated by inhibition of phosphodiesterase type 10A.

The invention further relates to a medicament, in particular amedicament which is suitable for the treatment of a disorder or acondition which can be treated by inhibition of phosphodiesterase type10A. The medicament comprises at least one compound of the formula I, asdescribed herein, or an N-oxide, a tautomer, or a hydrate or a prodrugof said compound I, or a pharmaceutically acceptable salt of thecompound of the formula I or a pharmaceutically acceptable salt of theN-oxide, the tautomer, the hydrate or the prodrug of compound of theformula I.

DETAILED DESCRIPTION OF THE INVENTION

The terms “compound of the formula I” and “compounds I” are used assynonyms.

The term “prodrugs” means compounds which are metabolized in vivo to thecompounds I of the invention. Typical examples of prodrugs are describedin C. G. Wermuth (editor): The Practice of Medicinal Chemistry, AcademicPress, San Diego, 1996, pages 671-715. These include for examplephosphates, carbamates, amino acids, esters, amides, peptides, ureas andthe like. Suitable prodrugs in the present case may be for examplederivatives of those compounds I carrying an OH or NH₂-group, where theOH or NH₂-group forms an ester/amide/peptide linkage, i.e. where one ofthe hydrogen atoms of the OH or NH₂-group is substituted by aC₁-C₄-alkylcarbonyl group, e.g. by acetyl, propionyl, n-propylcarbonyl,isopropylcarbonyl, n-butylcarbonyl or tert-butylcarbonyl (pivaloyl), bybenzoyl, or by an acyl group derived from an amino acid, e.g. glycine,alanine, serine, phenylalanine and the like, which is linked to theoxygen or nitrogen of the OH or NH₂-group via the carbonyl group of theamino acid. Further suitable prodrugs are alkylcarbonyloxyalkylcarbonates or carbamates of compounds I carrying an OH- or NH₂-group inwhich one of the hydrogen atoms of the OH- or NH₂-group has beenreplaced by a group of the formula —C(═O)—O—CHR^(p)—O—C(═O)—R^(q) inwhich R^(p) and R^(q) are independently of one another C₁-C₄-alkyl. Suchcarbonates and carbamates are described for example in J. Alexander, R.Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31(2),318-322. These groups can then be eliminated under metabolic conditionsand result in compounds I. Therefore, said prodrugs and theirpharmaceutically acceptable salts are also part of the invention.

The term “pharmaceutically acceptable salts” refers to cationic oranionic salts compounds, wherein the counter ion is derived frompharmaceutically acceptable non-toxic bases or acids including inorganicor organic bases and inorganic or organic acids.

When the compound of formula I or its prodrug, tautomer, hydrate orN-oxide is acidic, salts may be prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic and organic bases. Saltsderived from inorganic bases include salts, wherein the counter ion isaluminium, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc ion and thelike. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium ions. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of formula I or its prodrug, tautomer, hydrate orN-oxide is basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, trifluoroacetic acid, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, fumaric, and tartaric acids. It will be understoodthat, as used herein, references to the compounds of formula I are meantto also include the pharmaceutically acceptable salts.

The compounds of the invention may be in the form of a mixture ofdiastereomers, or of a mixture of diastereomers in which one of the twodiastereomers is enriched, or of essentially diastereomerically purecompounds (diastereomeric excess de>90%). The compounds are preferablyin the form of essentially diastereomerically pure compounds(diastereomeric excess de>90%). The compounds I of the invention mayfurthermore be in the form of a mixture of enantiomers (for example asracemate), of a mixture of enantiomers in which one of the twoenantiomers is enriched, or essentially in enantiomerically purecompounds (enantiomeric excess ee>90%). However, the compounds of theinvention are frequently prone to racemization in relation to thestereochemistry of the carbon atom which carries the radical R¹, so thatmixtures are frequently obtained in relation to this carbon atom, orcompounds which exhibit a uniform stereochemistry in relation to this Catom form mixtures under physiological conditions. However, in relationto other stereocenters and the occurrence, associated therewith, ofenantiomers and diastereomers, it is preferred to employ the compoundsenantiomerically pure or diastereomerically pure.

The present invention moreover relates to compounds as defined herein,wherein one or more of the atoms depicted in formula I have beenreplaced by its stable, preferably non-radioactive isotope (e.g.,hydrogen by deuterium, ¹²C by ¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) andpreferably wherein at least one hydrogen atom has been replaced by adeuterium atom. Of course, the compounds according to the inventioncontain more of the respective isotope than this naturally occurs andthus is anyway present in the compounds I.

The compounds of the formula I and their salts in the solid form mayexist in more than one crystal structure (polymorphism), and may also bein the form of hydrates or other solvates. The present inventionincludes any polymorph of the compound I or its salt as well as anyhydrate or other solvate.

In the context of the present description, unless stated otherwise, theterms “alkyl”, “alkenyl”, “alkoxy”, “alkenyloxy”, “fluoroalkyl”,“fluoroalkoxy”, “cycloalkyl”, “fluorinated cycloalkyl”, “alkylene”,“alkandiyl”, “hetaryl” and radicals derived therefrom, such as“hydroxylalkyl”, “alkoxylalkyl”, “alkoxyalkoxy”, “cycloalkylalkyl” and“fluorinated cycloalkylalkyl” and “hetarylalkyl” represent groups ofindividual radicals. The groups of noncyclic radicals “alkyl”,“alkenyl”, “alkoxy”, “alkenyloxy”, “fluoroalkyl”, “fluoroalkoxy”,“alkylene”, “alkandiyl”, and the groups of radicals derived therefromalways include both unbranched and branched “alkyl”, “alkenyl”,“alkoxy”, “alkenyloxy”, “fluoroalkyl”, “fluoroalkoxy”, “alkylene” and“alkandiyl”, respectively.

The prefix C_(n)—C_(m)— indicates the respective number of carbons inthe hydrocarbon unit. Unless indicated otherwise, fluorinatedsubstituents preferably have one to five identical or different fluorineatoms.

The term “halogen” designates in each case, fluorine, bromine, chlorineor iodine, specifically fluorine, chlorine or bromine.

Examples of other meanings are:

Alkyl, and the alkyl moieties for example in alkylcarbonyl,alkylsulfanyl, alkylsulfonyl, alkylsulfanylalkyl andalkylsulfanylalkoxy: saturated, straight-chain or branched hydrocarbonradicals having one or more C atoms, e.g. 1 to 10, 1 to 8, 1 to 6 or 1to 4 carbon atoms. Examples of C₁-C₄-alkyl are methyl, ethyl, propyl,1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and1,1-dimethylethyl. C₁-C₆-alkyl are, apart those mentioned forC₁-C₄-alkyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Examples forC₁-C₈-alkyl or C₂-C₉-alkyl are, apart those mentioned for C₁-C₆-alkyl,n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl,1-methyloctyl, 2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl,1,2-dimethylhexyl and 1-propylpentyl, 2-propylpentyl.

Fluoroalkyl and the fluoroalkyl moieties for example influoroalkylsulfonyl: an alkyl radical having ordinarily 1 to 4 C atoms,in particular 1 or 2 C-atoms (C₁-C₂-fluoroalkyl) as mentioned above,whose hydrogen atoms are partly or completely replaced by fluorine atomssuch as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl,2,2-trifluoro-1-methylethyl, 2-fluoropropyl, 3-fluoropropyl,2,2-difluoropropyl, 2,3-difluoropropyl, 3,3,3-trifluoropropyl,2,3,3,3-pentafluoropropyl, heptafluoropropyl,1-(fluoromethyl)-2-fluoroethyl, 4-fluorobutyl, and nonafluorobutyl.

Cycloalkyl, and the cycloalkyl moieties for example in cycloalkoxy,cycloalkyl-C₁-C₄-alkyl or cycloalkyl-C₁-C₄-alkoxy: monocyclic, saturatedhydrocarbon groups having three or more C atoms, e.g. 3, 4, 5, 6, 7 or 8carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Fluorinated cycloalkyl, and the flourinted cycloalkyl moieties forexample in fluorinated cycloalkoxy or fluorinatedcycloalkyl-C₁-C₄-alkyl: monocyclic, saturated hydrocarbon groups havingthree or more C atoms, e.g. 3, 4, 5, 6, 7 or 8 carbon ring members, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein at least one, e.g. 1, 2, 3, 4, 5 or 6 of the hydrogen atoms arereplaced by fluorine atoms, examples including 1-fluorocyclopropyl,2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl,2,3-difluorocyclopropyl, etc.

Cycloalkoxy: a cycloalkyl radical as defined above which is linked viaan oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy orcyclohexyloxy.

Cycloalkylalkyl: a cycloalkyl radical as defined above which is linkedvia an alkylene group, in particular via a methylene, 1,1-ethylene or1,2-ethylene group, e.g. cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethy, cyclohexylmethyl, 1-cyclopropylethyl,1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl or2-cyclohexylethyl.

Fluorinated cycloalkylalkyl: a fluorinated cycloalkyl radical as definedabove which is linked via an alkylene group, in particular via amethylene, 1,1-ethylene or 1,2-ethylene group, e.g.1-fluorocyclopropylmethyl, 2-fluorocyclopropylmethyl,2,2-difluorocyclopropylmethyl, 1,2-difluorocyclopropylmethyl,2,3-difluorocyclopropylmethyl, 1-(1-fluorocyclopropyl)ethyl,1-(2-fluorocyclopropyl)ethyl, 1-(2,2-difluorocyclopropyl)ethyl,1-(1,2-difluorocyclopropyl)ethyl, 1-(2,3-difluorocyclopropyl)ethyl,2-(1-fluorocyclopropyl)ethyl, 2-(2-fluorocyclopropyl)ethyl,2-(2,2-difluorocyclopropyl)ethyl, 2-(1,2-difluorocyclopropyl)ethyl or2-(2,3-difluorocyclopropyl)ethyl.

Alkenyl, and alkenyl moieties for example in alkenyloxy:monounsaturated, straight-chain or branched hydrocarbon radicals havingtwo or more C atoms, e.g. 2 to 4 carbon atoms and one C═C-double bond inany position, e.g. C₂-C₄-alkenyl such as ethenyl, 1-propenyl,2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl and2-methyl-2-propenyl.

Alkoxy or alkoxy moieties for example in alkoxyalkyl and alkoxyalkoxy:

an alkyl radical as defined above ordinarily having 1 to 6 C atoms,preferably 1 to 4 C atoms, which is connected to the remainder of themolecule via an O atom: e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy,butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

Fluoroalkoxy: alkoxy as described above, in which the hydrogen atoms ofthese groups are partly or completely replaced by fluorine atoms, i.e.for example C₁-C₄-fluoroalkoxy, in particular C₁-C₂-fluoroalkoxy, suchas fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy,2,3-difluoropropoxy, 3,3,3-trifluoropropoxy,2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy,1-(fluoromethyl)-2-fluoroethoxy, specifically fluoromethoxy,difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, or2,2,2-trifluoroethoxy.

Hydroxyalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, inwhich one hydrogen atom is replaced by an OH radical. Examples thereofare CH₂—OH, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl,2-hydroxypropyl, 1-methyl-1-hydroxyethyl, 1-methyl-2-hydroxyethyl,3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl,1-methyl-2-hydroxypropyl, 1,1-dimethyl-2-hydroxyetyl,1-methyl-1-hydroxypropyl etc.

Alkylsulfanyl: alkyl as defined above preferably having 1 to 4 C atoms,which is connected via a sulfur atom to the remainder of the molecule,e.g. methylsulfanyl, ethylsulfanyl, n-propylsulfanyl and the like.

Alkoxyalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in whichone hydrogen atom is replaced by an alkoxy radical ordinarily having 1to 4 C atoms. Examples thereof are CH₂—OCH₃, CH₂—OC₂H₅, n-propoxymethyl,CH₂—OCH(CH₃)₂, n-butoxymethyl, (1-methylpropoxy)methyl,(2-methylpropoxy)methyl, CH₂—OC(CH₃)₃, 2-(methoxy)ethyl,2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(1-methylethoxy)ethyl,2-(n-butoxy)ethyl, 2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl,2-(1,1-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl,2-(n-propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl,2-(1-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl,2-(1,1-dimethylethoxy)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl,3-(n-propoxy)propyl, 3-(1-methylethoxy)propyl, 3-(n-butoxy)propyl,3-(1-methylpropoxy)propyl, 3-(2-methylpropoxy)propyl,3-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl,2-(n-propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl,2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl,2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl,3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl,3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl,3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl,4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl,4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl,4-(1,1-dimethylethoxy)butyl, etc.

Alkoxyalkoxy: an alkoxyalkyl radical as defined above ordinarily having1 to 4 C atoms both in the alkoxy and the alkyl moiety which isconnected to the remainder of the molecule via an O atom: Examplesthereof are OCH₂—OCH₃, OCH₂—OC₂H₅, n-propoxymethoxy, OCH₂—OCH(CH₃)₂,n-butoxymethoxy, (1-methylpropoxy)methoxy, (2-methylpropoxy)methoxy,OCH₂—OC(CH₃)₃, 2-(methoxy)ethoxy, 2-(ethoxy)ethoxy, 2-(n-propoxy)ethoxy,2-(1-methylethoxy)ethoxy, 2-(n-butoxy)ethoxy, 2-(1-methylpropoxy)ethoxy,2-(2-methylpropoxy)ethoxy, 2-(1,1-dimethyl-ethoxy)ethoxy, etc.

Cycloalkylalkoxy: an alkoxy radical ordinarily having 1 to 4 C atoms,preferably 1 to 2 C atoms, in which one hydrogen atom is replaced by acycloalkyl radical ordinarily having 3 to 6 C atoms as defined above.Examples thereof are cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy,cyclobutylethoxy, cyclopentylethoxy, cyclohexylethoxy and the like.

“Alkylen” or “alkanediyl”: a saturated hydrocarbon chain havingordinarily from 1 to 4 carbon atoms, such as methylen (—CH₂—),1,2-ethylen (—CH₂CH₂—), 1,1-ethanediyl (—CH(CH₃)—), 1,2-propanediyl,1,3-propanediyl, 1,4-butanediyl, 1,2-butanediyl, 1,3-butanediyl,1-methyl-1,2-propanediyl, 2-methyl-1,3-propanediyl,1-methyl-1,1-ethanediyl, 1-methyl-1,2-propanediyl etc.

Saturated or partially unsaturated 5- to 7-membered monocarbocyclicradicals include cycloalkyl as defined above and cycloalkenyl havingordinarily from 4 to 7 carbon atoms as ring members, e.g.1-cyclobuten-1-yl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl,1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,2-cycloheptenyl, 3-cycloheptenyl.

Heterocyclyl: a heterocyclic radical which may be saturated or partlyunsaturated and which may be a monocyclic heterocyclic radicalordinarily having 3, 4, 5, 6, 7 or 8 ring atoms or a heterobicyclicradical ordinarily having 7, 8, 9 or 10 ring atoms, where ordinarily 1,2, 3 or 4, in particular 1, 2 or 3, of the ring atoms are heteroatomssuch as N, S or O, or heteroatom groups such as S(═O) or S(═O)₂ besidescarbon atoms as ring members.

Examples of saturated heteromonocycles are in particular:

-   -   Saturated heteromonocyclic radical which ordinarily has 3, 4, 5,        6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms        are heteroatoms such as N, S or O, besides carbon atoms as ring        members. These include for example:    -   C-bonded, 3- or 4-membered saturated rings such as 2-oxiranyl,        2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl,        1-azetidinyl, 2-azetidinyl.    -   C-bonded, 5-membered saturated rings such as        tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,        tetrahydrothien-2-yl, tetrahydrothien-3-yl,        tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,        tetrahydropyrazol-3-yl, tetrahydropyrazol-4-yl,        tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,        tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl,        1,2-oxathiolan-4-yl, 1,2-oxathiolan-5-yl,        tetrahydroisothiazol-3-yl, tetrahydroisothiazol-4-yl,        tetrahydroisothiazol-5-yl, 1,2-dithiolan-3-yl,        1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,        tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl,        tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl,        tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,        tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,        1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,        1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl.    -   C-bonded, 6-membered saturated rings such as:        tetrahydropyran-2-yl, tetrahydropyran-3-yl,        tetrahydropyran-4-yl, piperidin-2-yl, piperidin-3-yl,        piperidin-4-yl, tetrahydrothiopyran-2-yl,        tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl,        1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl,        1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl,        1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl,        1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl,        1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl,        1,2-dithian-4-yl, hexahydropyrimidin-2-yl,        hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl,        hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,        hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,        tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,        tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,        tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,        tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,        tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,        tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,        tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,        tetrahydro-1,2-oxazin-6-yl.    -   N-bonded, 5-membered saturated rings such as:        tetrahydropyrrol-1-yl, tetrahydropyrazol-1-yl,        tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl,        tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl,        tetrahydrothiazol-3-yl.    -   N-bonded, 6-membered saturated rings such as: piperidin-1-yl,        hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl,        hexahydro-pyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl,        tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl,        tetrahydro-1,4-oxazin-4-yl, tetrahydro-1,2-oxazin-2-yl.    -   Unsaturated heteromonocyclic radicals which ordinarily have 4,        5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring        atoms are heteroatoms such as N, S or O, besides carbon atoms as        ring members. These include for example:    -   C-bonded, 5-membered, partially unsaturated rings such as:        2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl,        2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl,        4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl,        2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl,        2,5-dihydrothien-2-yl, 2,5-dihydrothien-3-yl,        4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl,        2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl,        2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl,        4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl,        3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl,        3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl,        4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl,        4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl,        2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl,        4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl,        4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl,        2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl,        2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl,        2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl,        4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl,        2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl,        2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl,        2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl,        4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl,        4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl,        2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl,        2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl,        4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl,        4,5-dihydrooxazol-5-yl, 2,5-dihydrooxazol-2-yl,        2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl,        2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl,        2,3-dihydrooxazol-5-yl, 4,5-dihydrothiazol-2-yl,        4,5-dihydrothiazol-4-yl, 4,5-dihydrothiazol-5-yl,        2,5-dihydrothiazol-2-yl, 2,5-dihydrothiazol-4-yl,        2,5-dihydrothiazol-5-yl, 2,3-dihydrothiazol-2-yl,        2,3-dihydrothiazol-4-yl, 2,3-dihydrothiazol-5-yl,        1,3-dioxol-2-yl, 1,3-dioxol-4-yl, 1,3-dithiol-2-yl,        1,3-dithiol-4-yl, 1,3-oxathiol-2-yl, 1,3-oxathiol-4-yl,        1,3-oxathiol-5-yl.    -   C-bonded, 6-membered, partially unsaturated rings such as:        2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl,        2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl,        2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl,        2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl,        2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl,        1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl,        1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl,        1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl,        2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl,        2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl,        2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl,        2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl,        2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl,        1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl,        1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetra-hydropyridin-6-yl,        2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl,        2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl,        2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl,        4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl,        4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl,        1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl,        2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl,        2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl,        2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1,2-dihydropyridin-2-yl,        1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl,        1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl,        3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl,        3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl,        3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl,        2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl,        2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl,        2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl,        2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl,        2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2-oxazin-3-yl,        2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5-yl,        2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl,        2H-5,6-dihydro-1,2-thiazin-4-yl,        2H-5,6-dihydro-1,2-thiazin-5-yl,        2H-5,6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl,        4H-5,6-dihydro-1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl,        4H-5,6-dihydro-1,2-oxazin-6-yl, 4H-5,6-dihydro-1,2-thiazin-3-yl,        4H-5,6-dihydro-1,2-thiazin-4-yl,        4H-5,6-dihydro-1,2-thiazin-5-yl,        4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3,6-dihydro-1,2-oxazin-3-yl,        2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6-dihydro-1,2-oxazin-5-yl,        2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro-1,2-thiazin-3-yl,        2H-3,6-dihydro-1,2-thiazin-4-yl,        2H-3,6-dihydro-1,2-thiazin-5-yl,        2H-3,6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3-yl,        2H-3,4-dihydro-1,2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl,        2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-yl,        2H-3,4-dihydro-1,2-thiazin-4-yl,        2H-3,4-dihydro-1,2-thiazin-5-yl,        2H-3,4-dihydro-1,2-thiazin-6-yl,        2,3,4,5-tetrahydropyridazin-3-yl,        2,3,4,5-tetrahydropyridazin-4-yl,        2,3,4,5-tetrahydropyridazin-5-yl,        2,3,4,5-tetrahydropyridazin-6-yl,        3,4,5,6-tetrahydropyridazin-3-yl,        3,4,5,6-tetrahydropyridazin-4-yl,        1,2,5,6-tetrahydropyridazin-3-yl,        1,2,5,6-tetrahydropyridazin-4-yl,        1,2,5,6-tetrahydropyridazin-5-yl,        1,2,5,6-tetrahydropyridazin-6-yl,        1,2,3,6-tetrahydropyridazin-3-yl,        1,2,3,6-tetrahydropyridazin-4-yl,        4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl,        4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl,        4H-5,6-dihydro-1,3-thiazin-2-yl,        4H-5,6-dihydro-1,3-thiazin-4-yl,        4H-5,6-dihydro-1,3-thiazin-5-yl,        4H-5,6-dihydro-1,3-thiazin-6-yl,        3,4,5-6-tetrahydropyrimidin-2-yl,        3,4,5,6-tetrahydropyrimidin-4-yl,        3,4,5,6-tetra-hydropyrimidin-5-yl,        3,4,5,6-tetrahydropyrimidin-6-yl,        1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl,        1,2,3,4-tetrahydropyrimidin-2-yl,        1,2,3,4-tetrahydropyrimidin-4-yl,        1,2,3,4-tetrahydropyrimidin-5-yl,        1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4-thiazin-2-yl,        2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl,        2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl,        2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl,        2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl,        2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl,        4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl,        4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1,3-thiazin-6-yl,        6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl,        6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl,        6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl, 2H-1,4-oxazin-2-yl,        2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl,        2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4-thiazin-5-yl,        2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl,        4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,        1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,        1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,        1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,        1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,        1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,        1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,        1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,        3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or        3,4-dihydropyrimidin-6-yl.    -   N-bonded, 5-membered, partially unsaturated rings such as:        2,3-dihydro-1H-pyrrol-1-yl, 2, 5-dihydro-1H-pyrrol-1-yl, 4,        5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl, 2,        3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl,        2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl,        2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl,        2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl,        2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl.    -   N-bonded, 6-membered, partially unsaturated rings such as:        1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl,        1,4-dihydropyridin-1-yl, 1,2-dihydropyridin-1-yl,        2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl,        2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl,        2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl,        2,3,4,5-tetrahydropyridazin-2-yl,        1,2,5,6-tetrahydropyridazin-1-yl,        1,2,5,6-tetrahydropyridazin-2-yl,        1,2,3,6-tetrahydropyridazin-1-yl,        3,4,5,6-tetrahydropyrimidin-3-yl,        1,2,3,4-tetrahydropyrazin-1-yl,        1,2,3,4-tetrahydropyrimidin-1-yl,        1,2,3,4-tetrahydro-pyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl,        2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl, 4H-1,4-oxazin-4-yl,        4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,        1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,        1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl.

Heterocyclyloxy: a heterocyclyl radical as defined above which isattached to the remainder of the molecule via an oxygen atom. Theheterocyclyl radical ordinarily has 3, 4, 5, 6 or 7 ring atoms, in whichbesides carbon atoms as ring members ordinarily 1, 2 or 3, in particular1 or 2, of the ring atoms are heteroatoms such as N, S or O, inparticular 5- to 7-membered heterocycloyloxy, where heterocyclyl has 1or 2 heteroatoms selected from O, S and N as ring members, for exampletetrahydrofuran-2-yloxy, tetrahydrofuran-3-yloxy,tetrahydrothiophen-2-yloxy or tetrahydrothiophen-3-yloxy.

Heterocyclyl-C₁-C₄-alkoxy: a C₁-C₄-alkoxy group as defined above inwhich one hydrogen atom is replaced by a heterocyclyl radical as definedabove. The heterocyclyl radical ordinarily has 3, 4, 5, 6 or 7 ringatoms, in which besides carbon atoms as ring members ordinarily 1, 2 or3, in particular 1 or 2, of the ring atoms are heteroatoms such as N, Sor O. In particular, 5- to 7-membered heterocyclyl-C₁-C₂-alkoxy, whereheterocyclyl has 1 or 2 heteroatoms selected from O, S and N as ringmembers, for example tetrahydrofuran-2-yl-methoxy,tetrahydrofuran-2-yl-ethoxy, tetrahydrofuran-3-ylmethoxy,tetrahydrofuran-3-ylethoxy, tetrahydrothiophen-2-ylmethoxy,tetrahydrothiophen-2-ylethoxy, tetrahydrothiophen-3-ylmethoxy,tetrahydrothiophen-3-ylethoxy.

Hetaryl: a 5- or 6-membered aromatic heteromonocyclic radical (alsotermed 5- or 6-membered monocyclic hetaryl) which ordinarily has 1, 2, 3or 4 heteroatoms as ring members, which are selected from O, S and N,and which has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatomselected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogenatoms as ring members besides carbon atoms as ring members and a 8-, 9-or 10-membered aromatic heterobicyclic radical (also termed 8-, 9- or10-membered bicyclic hetaryl) which ordinarily has 1, 2, 3 or 4heteroatoms as ring members, which are selected from O, S and N, andwhich has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatomselected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogenatoms as ring members besides carbon atoms as ring members: for example

-   -   C-bonded, 5-membered monocyclic hetaryl having 1, 2 or 3 or 4        nitrogen atoms or a heteroatom selected from oxygen and sulfur        and, if appropriate, having 1, 2 or 3 nitrogen atoms as ring        members, such as:    -   2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl,        pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl,        isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,        isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl,        oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl,        thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,        1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl,        1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl,        1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,        1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl,        1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl.    -   C-bonded, 6-membered monocyclic hetaryl having 1, 2 or 3        nitrogen atoms as ring members, such as:    -   pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl,        pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,        pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,        1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl.    -   N-bonded, 5-membered heteroaromatic radicals having 1, 2, 3 or 4        nitrogen atoms as ring members, such as:    -   pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,        1,2,4-triazol-1-yl, tetrazol-1-yl.    -   bicyclic 8-, 9-10-membered hetaryl, hetaryl which has one of the        aforementioned 5- or 6-membered heteroaromatic rings and a        further aromatic carbocycle or 5- or 6-membered heterocycle        fused thereto, for example a fused benzene, thiophene, furane,        pyrrole, pyrazole, imidazole, pyridine or pyrimidine ring. These        bicyclic hetaryl include for example quinolinyl, isoquinolinyl,        cinnolinyl, indolyl, indolizynyl, isoindolyl, indazolyl,        benzofuryl, benzothienyl, benzo[b]thiazolyl, benzoxazolyl,        benzthiazolyl, benzimidazolyl, imidazo[1,2-a]pyridine-2-yl,        thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and        1,2,4-triazolo[1,5-a]pyridine-2-yl.

Hetarylalkyl: a hetaryl radical as defined above which is linked via analkylene group, in particular via a methylene, 1,1-ethylene or1,2-ethylene group, to the remainder of the molecule.

5- to 6-membered hetaryl-C₁-C₄-alkoxy: a C₁-C₄-alkoxy group as definedabove which carries a 5- to 6-membered hetaryl radical as defined above,where the hetaryl radical has ordinarily 1, 2 or 3, in particular 1 or2, heteroatoms as ring members which are selected from O, S and N.Examples are furan-2-ylmethoxy, furan-3-ylmethoxy, furan-2-ylethoxy,furan-3-ylethoxy, thiophen-2-ylmethoxy, thiophen-3-ylmethoxy,thiophen-2-ylethoxy and thiophen-3-ylethoxy. The expression “optionallysubstituted” in the context of the present invention means that therespective moiety is unsubstituted or has 1, 2 or 3, in particular 1,substituents which are selected from halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, OH, SH, CN, CF₃, O—CF₃, COOH, O—CH₂—COOH, C₁-C₆-alkoxy,C₁-C₄-haloalkoxy, C₁-C₆-alkylthio, C₃-C₇-cycloalkyl, COO—C₁-C₆-alkyl,CONH₂, CONH—C₁-C₆-alkyl, SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂,SO₂N—(C₁-C₆-alkyl)₂, NH—SO₂—C₁-C₆-alkyl, NH—CO—C₁-C₆-alkyl,SO₂—C₁-C₆-alkyl, O-phenyl, O—CH₂-phenyl, CONH-phenyl, SO₂NH-phenyl,CONH-hetaryl, SO₂NH-hetaryl, SO₂-phenyl, NH—SO₂-phenyl, NH—CO-phenyl,NH—SO₂-hetaryl and NH—CO-hetaryl, where phenyl and hetaryl in the last11 radicals mentioned are unsubstituted or may have 1, 2 or 3substituents which are selected from halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

In particular embodiments of the invention, R^(h) is selected from thegroup consisting of halogen, CN, OH, C₁-C₄-alkyl, fluorinatedC₁-C₄-alkyl, C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy, C₃-C₆-cycloalkyl,fluorinated C₃-C₆-cycloalkyl, N(R^(b))(R^(c)),C₁-C₄-alkyl-N(R^(b))(R^(c)), C(O)O—R^(d), C(O)N(R^(e))(R^(f)),N(R^(ee))S(O)₂(R^(ff)) and S(O)₂N(R^(e))(R^(f)).

In relation to their use as inhibitors of PDE10A, the variables X¹, X²,Y, R¹, R², R³ and R⁴ in formula I preferably have the followingmeanings, where these represent, both considered on their own and incombination with at least one other or all, special embodiments of thecompounds of the formula I:

R¹ is preferably C₂-C₈-alkyl, C₃-C₈-cycloalkyl orC₃-C₈-cycloalkylmethyl, in particular C₃-C₈-cycloalkylmethyl orespecially C₂-C₈-alkyl. Particularly, R¹ is alkyl of the formulaCHR^(1a)R^(1b), where R^(1a) is selected from the group consisting ofhydrogen and C₁-C₃-alkyl, in particular methyl, ethyl, n-propyl andwhere R^(1b) is selected from the group consisting of C₁-C₄-alkyl, inparticular methyl, ethyl, n-propyl or n-butyl. Particular examples of R¹are selected from the group consisting of ethyl, isopropyl,1-methylpropyl and 1-ethylpropyl.

Particular embodiments of the invention also relate to compounds, whereR¹ is a moiety Z¹—Ar¹, where Z¹ and Ar¹ are as defined above and whereZ¹ is preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4hydrogen atoms may be replaced by a fluorine atom. According to aspecific embodiment, Z¹ is 1,2-ethanediyl which is unsubstituted or1,3-propanediyl which is unsubstituted. In these embodiments, Ar¹ ispreferably monocyclic 6-membered hetaryl or bicyclic 9- or 10-memberedhetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring members whichare selected from O, S and N, where mono- and bicyclic hetaryl areunsubstituted or may carry 1, 2 or 3 identical or different substituentsR^(h).

Ar¹ is preferably selected from the group consisting of C-bound6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ringmembers, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogenatoms as ring members and optionally a further heteroatom selected fromO, S and N as ring member, where monocyclic hetaryl and bicyclic hetarylmay be unsubstituted or may carry 1, 2 or 3 substituents R^(h), inparticular 0, 1 or 2 substituents R^(h). In this regard, R^(h) ispreferably selected from halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl,C₁-C₄-alkoxy, C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl, and fluorinatedC₃-C₆-cycloalkyl. In this regard, R^(h) is in particular selected fromfluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.

Ar¹ is in particular selected from the group consisting of fusedbicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members andoptionally a further heteroatom selected from O, S and N as ring memberand which may be unsubstituted or may carry 1, 2 or 3 substituentsR^(h), in particular 0, 1 or 2 substituents R^(h) as defined above.Amongst these, particular preference is given to those compounds, wherethe Ar¹ radical has at least one imino-nitrogen as ring member, which islocated in the position adjacent to carbon atom bound to the group Z¹.Amongst these, particular preference is given to those, where Ar¹ isselected from the group consisting of C-bound, fused bicyclic hetaryl,which has 1 or 2 nitrogen atoms as ring members and optionally a furtherheteroatom selected from O, S and N as ring member, where bicyclichetaryl may be unsubstituted or may carry 1, 2 or 3 substituents R^(h),in particular 0, 1 or 2 substituents R^(h). In this regard, R^(h) ispreferably selected from halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl,C₁-C₄-alkoxy, C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl and fluorinatedC₃-C₆-cycloalkyl. In this regard, R^(h) is in particular selected fromfluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.

Particular examples of Ar¹ are selected from the group consisting of2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl,3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl,2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl,benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl,1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl,thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicalsare unsubstituted or may carry 1, 2 or 3 radicals R^(h) as definedabove, which are in particular selected from the group consisting offluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, and fluorinated cyclopropyl.

In particular embodiments, R² is a radical of the formula CR²¹R²²R²³,where R²¹, R²² and R²³ are as defined above and where R²¹ is inparticular different from hydrogen.

In other particular embodiments, R² is a phenyl or 5- or 6-memberedhetaryl radical having 1, 2 or 3 heteroatoms as ring members which areselected from O, S and N, where phenyl and monocyclic hetaryl areunsubstituted or may carry 1, 2 or 3 identical or different substituentsR^(a) as defined above.

In the particular embodiments, where R² is a radical of the formulaCR²¹R²²R²³, where R²¹, R²² and R²³ are as defined above or where R² is aphenyl or 5- or 6-membered hetaryl radical having 1, 2 or 3 heteroatomsas ring members which are selected from O, S and N, where phenyl andmonocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical ordifferent substituents R^(a) as defined above, the radical R³ ispreferably selected from the group consisting of hydrogen andC₁-C₄-alkyl. In these embodiments, R³ is in particular hydrogen.

In the particular embodiments, where R² is a radical of the formulaCR²¹R²²R²³, a particular group of embodiments relates to compounds,where the radicals R²¹, R²² and R²³ have the following meanings:

-   R²¹ is selected from the group consisting of C₁-C₈-alkyl,    trimethylsilyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,    hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)),    (CH₂)_(m)C(O)O—R^(d), (CH₂)_(m)C(O)N(R^(e))(R^(f)) and Z²—Ar²,-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,    hydroxy-C₁-C₄-alkyl and C₁-C₄-alkyl-N(R^(b))(R^(c)), or-   R²³ is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl and C₁-C₄-fluoroalkyl;

In the particular embodiments, where R² is a radical of the formulaCR²¹R²²R²³, a particular group of embodiments relates to compounds,where the radicals R²¹, R²² and R²³ preferably have the followingmeanings, both considered on their own and in combination with at leastone other or all:

-   R²¹ is selected from the group consisting of C₂-C₈-alkyl,    trimethylsilyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl and Z²—Ar², where Z² and    Ar², where Z² and Ar² are as defined above and where Z² is    preferably a single bond or CH₂ and Ar² is preferably phenyl,    pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are    unsubstituted or which carry 1, 2 or 3 identical or different    substituents R^(h);-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, in particular hydrogen; and-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In the particular embodiments, where R² is a radical of the formulaCR²¹R²²R²³, a particular group of embodiments relates to compounds,where the radicals R²¹, R²² and R²³ preferably have the followingmeanings, both considered on their own and in combination with at leastone other or all:

-   R²¹ is selected from the group consisting of C₂-C₈-alkyl,    trimethylsilyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl, and where R²¹ is in    particular C₂-C₄-alkyl;-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, in particular methyl or hydrogen; and-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In the particular embodiments, where R² is a radical of the formulaCR²¹R²²R²³, another particular group of embodiments relates tocompounds, where the radicals R²¹, R²² and R²³ preferably have thefollowing meanings, both considered on their own and in combination withat least one other or all:

-   R²¹ is a radical Z²—Ar², where Z² and Ar² are as defined above and    where Z² is preferably a single bond or CH₂ and Ar² is preferably    phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl,    which are unsubstituted or which carry 1, 2 or 3 identical or    different substituents R^(h), particular examples of R²¹ being 2-,    3- or 4-fluorophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or    4-methoxyphenyl, 2,3-difluorophenyl, 3,5-difluorophenyl,    3,4-difluorophenyl, thiazol-2-yl, thiazol-4-yl,    1,3,4-thiadiazol-2-yl, 2-(1-morpholinosulfonyl)phenyl,    3-(1-morpholinosulfonyl)phenyl,    2-(4-methylpiperazin-1-ylsulfonyl)phenyl or    3-(4-methylpiperazin-1-ylsulfonyl)phenyl.-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, in particular methyl or hydrogen; and-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In the particular embodiments, where R² is a radical of the formulaCR²¹R²²R²³, a further group of embodiments relates to compounds, wherethe radicals R²¹ and R²² together with the carbon atom, to which theyare bound form a saturated 5-, 6- or 7-membered carbocyclic ring, suchas cyclopentyl, cyclohexyl or cycloheptyl, especially cyclopentyl, or asaturated 5-, 6- or 7-membered heterocyclic ring which has 1, 2 or 3heteroatoms or heteroatom containing groups selected from the group ofO, N, S, SO and SO₂ as ring members, especially 2- or 3-tetrahydrofurylor 2- or 3-tetrahydrothienyl, where the carbocyclic ring and theheterocyclic ring may be unsubstituted or may be substituted by 1, 2 or3 identical or different substituents R^(g), and where the carbocyclicring and the heterocyclic ring may carry a fused benzene ring or a fused5- or 6-membered heteroaromatic ring, where the fused rings themselvesare unsubstituted or carry 1, 2 or 3 substituents R^(h), and whereR^(g), R^(h) and R²³ are as defined above and where R²³ is in particularhydrogen or C₁-C₄-alkyl, such as methyl, or especially hydrogen.

In the particular embodiments, where R² is a radical of the formulaCR²¹R²²R²³, a further particular group of embodiments relates tocompounds, where the radicals R²¹, R²² and R²³ preferably have thefollowing meanings, both considered on their own and in combination withat least one other or all:

-   R²¹ and R²² together with the carbon atom, to which they are bound    form a saturated 5-, 6- or 7-membered carbocyclic radical, namely a    cyclopentyl, cyclohexyl or cycloheptyl radical or a    3-tetrahydrofuryl or 3-tetrahydrothienyl, where the 5- to 7-membered    carbocyclic ring and the 3-tetrahydrofuryl or 3-tetrahydrothienyl    ring carry a fused benzene ring or a fused 5- or 6-membered    heteroaromatic ring, such as a fused thiophene or pyridine ring,    where the fused rings themselves are unsubstituted or carry 1, 2 or    3 substituents R^(h), and where R²¹ and R²² in particular form a    bicyclic radical selected from the group consisting of 5-indanyl,    6-indanyl, 5,6,7,8-tetrahydronaphthalin-5-yl,    5,6,7,8-tetrahydronaphthalin-6-yl,    6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl,    6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl,    5,6-dihydro-4H-cyclopenta[b]thiophene-4-yl,    6,7-dihydro-5H-[1]-pyrindin-6-yl, 3,4-dihydrobenzofuran-3-yl,    2,3-dihydrobenzothiophen-3-yl or where these bicyclic radicals are    in particular unsubstituted or where the aromatic moiety of these    rings carry 1, 2 or 3 substituents R^(h);-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In further particular embodiments of the invention R² and R³ togetherwith the nitrogen atom, to which they are bound form a saturated 4-, 5-,6- or 7-membered heterocyclic ring which, in addition to the nitrogenatom, may have 1 or 2 further heteroatoms or heteroatom containinggroups selected from the group of O, N, S, SO and SO₂ as ring members,e.g. a pyrrolidine, piperidine, morpholine, thiomorpholine or piperazinering, where the heterocyclic ring may be unsubstituted or may besubstituted by 1, 2 or 3 identical or different substituents R³¹, andwhere the heterocyclic ring may carry a fused benzene ring or a fused 5-or 6-membered heteroaromatic ring, such as a thiophene or pyridine ring,where the fused rings themselves are unsubstituted or carry 1, 2 or 3substituents R³², where R³¹ and R³² are as defined defined above.

R³¹ is in particular selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-alkoxy, halogen, phenyl and phenoxy, where the phenylring in thelast two mentioned radicals itself is unsubstituted or carries 1 or 2radicals selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-alkoxy, halogen.

R³² is in particular selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-alkoxy and halogen.

R⁴ is preferably C₁-C₄-alkyl and especially methyl.

Y is preferably O.

A particular group of embodiments of the invention relates to compoundsof the formula I, to their salts, N-oxides, tautomers, hydrates andprodrugs and to the salts of said N-oxides, tautomers, hydrates andprodrugs, where X² is C—R⁵. In this particular group of embodiments R⁵is preferably selected from the group consisting of hydrogen, fluorine,C₁-C₄-alkoxy or a radical O—Z⁵—Ar⁵, especially hydrogen, fluorine,methoxy or a radical O—Z⁵—Ar⁵. Amongst these compounds a firstembodiment relates to compounds of the formula I, to their salts,tautomers, hydrates and prodrugs and to the salts of said tautomers,hydrates and prodrugs, where R⁵ is hydrogen, fluorine, OH orC₁-C₄-alkoxy, especially hydrogen, fluorine, OH or methoxy, with methoxybeing particularly preferred.

Amongst these compounds a second embodiment relates to compounds of theformula I, to their salts, tautomers, hydrates and prodrugs and to thesalts of said tautomers, hydrates and prodrugs, where R⁵ is a radicalO—Z⁵—Ar⁵. In this second embodiment R⁴ is in particular C₁-C₄-alkyl,especially methyl.

In the second embodiment, Z⁵ is preferably 1,2-ethanediyl or1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced bya fluorine atom. According to a specific embodiment, Z⁵ is1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which isunsubstituted.

In the second embodiment, Ar⁵ is preferably selected from the groupconsisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl,which has 1 or 2 nitrogen atoms as ring members and optionally a furtherheteroatom selected from O, S and N as ring member, where monocyclichetaryl may be unsubstituted or may carry 1, 2 or 3 identical ordifferent substituents R^(k), in particular 0, 1 or 2 substituents R^(k)and bicyclic hetaryl may be unsubstituted or may carry 1 substituentR^(k), and 0, 1, 2 or 3 substituents R^(h), in particular 0, 1 or 2substituents R^(h). In this regard, R^(h) is preferably selected fromhalogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy,C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl, and fluorinated C₃-C₆-cycloalkyl.In this regard, R^(h) is in particular selected from fluorine, chlorine,methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl andfluorinated cyclopropyl.

Ar⁵ is in particular selected from the group consisting of fusedbicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members andoptionally a further heteroatom selected from O, S and N as ring memberand which may be unsubstituted or may carry 1 substituent R^(k) and/ormay carry 1, 2 or 3 substituents R^(h), in particular 0, 1 or 2substituents R^(h) as defined above. Amongst these, particularpreference is given to those compounds, where the Ar⁵ radical has atleast one imino-nitrogen as ring member, which is located in theposition adjacent to carbon atom bound to the group Z⁵. Amongst these,particular preference is given to those, where Ar⁵ is selected from thegroup consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2nitrogen atoms as ring members and optionally a further heteroatomselected from O, S and N as ring member, where bicyclic hetaryl may beunsubstituted or may carry 1 substituent R^(k) and/or may carry 1, 2 or3 substituents R^(h), in particular 0, 1 or 2 substituents R^(h). Inthis regard, R^(h) is preferably selected from halogen, C₁-C₄-alkyl,C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy, C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl andfluorinated C₃-C₆-cycloalkyl. In this regard, R^(h) is in particularselected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.

Particular examples of Ar⁵ are selected from the group consisting of2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl,3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl,2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl,benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl,1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl,thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicalsare unsubstituted or may carry 1, 2 or 3 radicals R^(h) as definedabove, which are in particular selected from the group consisting offluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, and fluorinated cyclopropyl.

Amongst these compounds a third embodiment relates to compounds of theformula I, to their salts, tautomers, hydrates and prodrugs and to thesalts of said tautomers, hydrates and prodrugs, where R⁴ is a radicalZ⁴—Ar⁴. In this third embodiment R⁵ is in particular hydrogen, fluorineor C₁-C₄-alkoxy, especially methoxy.

In the third embodiment, Z⁴ is preferably 1,2-ethanediyl or1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced bya fluorine atom. According to a specific embodiment, Z⁴ is1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which isunsubstituted.

In the third embodiment, Ar⁴ is preferably selected from the groupconsisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl,which has 1 or 2 nitrogen atoms as ring members and optionally a furtherheteroatom selected from O, S and N as ring member, where monocyclichetaryl may be unsubstituted or may carry 1, 2 or 3 identical ordifferent substituents R^(h), in particular 0, 1 or 2 substituents R^(h)and bicyclic hetaryl may be unsubstituted or may carry 1 substituentR^(h), and 0, 1, 2 or 3 substituents R^(h), in particular 0, 1 or 2substituents R^(h). In this regard, R^(h) is preferably selected fromhalogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy,C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl, and fluorinated C₃-C₆-cycloalkyl.In this regard, R^(h) is in particular selected from fluorine, chlorine,methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl andfluorinated cyclopropyl.

Ar⁴ is in particular selected from the group consisting of fusedbicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members andoptionally a further heteroatom selected from O, S and N as ring memberand which may be unsubstituted or may carry 1 substituent R^(k) and/ormay carry 1, 2 or 3 substituents R^(h), in particular 0, 1 or 2substituents R^(h) as defined above. Amongst these, particularpreference is given to those compounds, where the Ar⁴ radical has atleast one imino-nitrogen as ring member, which is located in theposition adjacent to carbon atom bound to the group Z⁴. Amongst these,particular preference is given to those, where Ar⁴ is selected from thegroup consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2nitrogen atoms as ring members and optionally a further heteroatomselected from O, S and N as ring member, where bicyclic hetaryl may beunsubstituted or may carry 1 substituent R^(k) and/or may carry 1, 2 or3 substituents R^(h), in particular 0, 1 or 2 substituents R^(h). Inthis regard, R^(h) is preferably selected from halogen, C₁-C₄-alkyl,C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy, C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl andfluorinated C₃-C₆-cycloalkyl. In this regard, R^(h) is in particularselected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.

Particular examples of Ar⁴ are selected from the group consisting of2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl,3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl,2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl,benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl,1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl,thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicalsare unsubstituted or may carry 1, 2 or 3 radicals R^(h) as definedabove, which are in particular selected from the group consisting offluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, and fluorinated cyclopropyl.

A first group of embodiments of the invention relates to compounds ofthe formula I, to their salts, N-oxides, tautomers, hydrates andprodrugs and to the salts of said N-oxides, tautomers, hydrates andprodrugs, where X¹ is C—H and X² is C—R⁵. In this first group, Y, R¹,R², R³, R⁴ and R⁵ are as defined above and preferably have the preferredor particular or special meanings given above. Amongst these compounds,a particular group of embodiments is represented by the followingformula Ia

where R¹, R², R³, R⁴ and R⁵ are as defined above.

A second group of embodiments of the invention relates to compounds ofthe formula I, to their salts, N-oxides, tautomers, hydrates andprodrugs and to the salts of said N-oxides, tautomers, hydrates andprodrugs, where X¹ is N and X² is C—R⁵. In this second group, Y, R¹, R²,R³, R⁴ and R⁵ are as defined above and preferably have the preferred orparticular or special meanings given above. Amongst these compounds, aparticular group of embodiments is represented by the following formulaIb

where R¹, R², R³, R⁴ and R⁵ are as defined above.

A particular group of embodiments of the invention relates to compoundsof the formulae Ia and Ib, to their salts, N-oxides, tautomers, hydratesand prodrugs and to the salts of said N-oxides, tautomers, hydrates andprodrugs, where R⁵ is preferably selected from the group consisting ofhydrogen, fluorine, C₁-C₄-alkoxy or a radical O—Z⁵—Ar⁵, especiallyhydrogen, fluorine, methoxy or a radical O—Z⁵—Ar⁵. Amongst thesecompounds a first embodiment relates to compounds of the formulae Ia andIb, to their salts, tautomers, hydrates and prodrugs and to the salts ofsaid tautomers, hydrates and prodrugs, where R⁵ is hydrogen, fluorine,OH or C₁-C₄-alkoxy, especially hydrogen, fluorine, OH or methoxy, withmethoxy being particularly preferred.

Amongst these compounds a second embodiment relates to compounds of theformula Ia and Ib, to their salts, tautomers, hydrates and prodrugs andto the salts of said tautomers, hydrates and prodrugs, where R⁵ is aradical O—Z⁵—Ar⁵, where Z⁵ and Ar⁵ are as defined above and having inparticular the preferred, particular or special meanings given above. Inthis second embodiment R⁴ is in particular C₁-C₄-alkyl, especiallymethyl.

In the second embodiment of formulae Ia and Ib, Z⁵ is preferably1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atomsmay be replaced by a fluorine atom. According to a specific embodiment,Z⁵ is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which isunsubstituted.

In the second embodiment of formulae Ia and Ib, Ar⁵ is preferablyselected from the group consisting of C-bound 6-membered monocyclichetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound,fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring membersand optionally a further heteroatom selected from O, S and N as ringmember, where monocyclic hetaryl may be unsubstituted or may carry 1, 2or 3 identical or different substituents R^(k), in particular 0, 1 or 2substituents R^(k) and bicyclic hetaryl may be unsubstituted or maycarry 1 substituent R^(k), and 0, 1, 2 or 3 substituents R^(h), inparticular 0, 1 or 2 substituents R^(h). In this regard, R^(h) ispreferably selected from halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl,C₁-C₄-alkoxy, C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl, and fluorinatedC₃-C₆-cycloalkyl. In this regard, R^(h) is in particular selected fromfluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.

In the second embodiment of formulae Ia and Ib, Ar⁵ is in particularselected from the group consisting of fused bicyclic hetaryl, which has1 or 2 nitrogen atoms as ring members and optionally a furtherheteroatom selected from O, S and N as ring member and which may beunsubstituted, or may carry 1 substituent R^(k) and/or may carry 1, 2 or3 substituents R^(h), in particular 0, 1 or 2 substituents R^(h) asdefined above. Amongst these, particular preference is given to thosecompounds, where the Ar⁵ radical has at least one imino-nitrogen as ringmember, which is located in the position adjacent to carbon atom boundto the group Z⁵. Amongst these, particular preference is given to those,where Ar⁵ is selected from the group consisting of C-bound, fusedbicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members andoptionally a further heteroatom selected from O, S and N as ring member,where bicyclic hetaryl may be unsubstituted, or may carry 1 substituentR^(k) and/or may carry 1, 2 or 3 substituents R^(h), in particular 0, 1or 2 substituents R^(h). In this regard, R^(h) is preferably selectedfrom halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy,C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl and fluorinated C₃-C₆-cycloalkyl. Inthis regard, R^(h) is in particular selected from fluorine, chlorine,methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl andfluorinated cyclopropyl.

In the second embodiment of formulae Ia and Ib, Ar⁵ is e.g. selectedfrom the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl,3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl,1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl,benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl,where the aforementioned radicals are unsubstituted or may carry 1, 2 or3 radicals R^(h) as defined above, which are in particular selected fromthe group consisting of fluorine, chlorine, methyl, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.

Amongst these compounds a third embodiment relates to compounds of theformula Ia and Ib, to their salts, tautomers, hydrates and prodrugs andto the salts of said tautomers, hydrates and prodrugs, where R⁴ is aradical Z⁴—Ar⁴, where Z⁴ and Ar⁴ are as defined above and having inparticular the preferred, particular or special meanings given above. Inthis third embodiment R⁵ is in particular hydrogen, fluorine or inparticular C₁-C₄-alkoxy, especially methoxy.

In the third embodiment of formulae Ia and Ib, Z⁴ is preferably1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atomsmay be replaced by a fluorine atom. According to a specific embodiment,Z⁴ is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which isunsubstituted.

In the third embodiment of formulae Ia and Ib, Ar⁴ is preferablyselected from the group consisting of C-bound 6-membered monocyclichetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound,fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring membersand optionally a further heteroatom selected from O, S and N as ringmember, where monocyclic hetaryl may be unsubstituted or may carry 1, 2or 3 substituents R^(k), in particular 0, 1 or 2 substituents R^(k) andbicyclic hetaryl may be unsubstituted or may carry 1 substituent R^(k),and 0, 1, 2 or 3 substituents R^(h), in particular 0, 1 or 2substituents R^(h). In this regard, R^(h) is preferably selected fromhalogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy,C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl, and fluorinated C₃-C₆-cycloalkyl.In this regard, R^(h) is in particular selected from fluorine, chlorine,methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl andfluorinated cyclopropyl.

In the third embodiment of formulae Ia and Ib, Ar⁴ is in particularselected from the group consisting of fused bicyclic hetaryl, which has1 or 2 nitrogen atoms as ring members and optionally a furtherheteroatom selected from O, S and N as ring member and which may beunsubstituted, or may carry 1 substituent R^(k) and/or may carry 1, 2 or3 substituents R^(h), in particular 0, 1 or 2 substituents R^(h) asdefined above. Amongst these, particular preference is given to thosecompounds, where the Ar⁴ radical has at least one imino-nitrogen as ringmember, which is located in the position adjacent to carbon atom boundto the group Z⁴. Amongst these, particular preference is given to those,where Ar⁴ is selected from the group consisting of C-bound, fusedbicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members andoptionally a further heteroatom selected from O, S and N as ring member,where bicyclic hetaryl may be unsubstituted, or may carry 1 substituentR^(k) and/or may carry 1, 2 or 3 substituents R^(h), in particular 0, 1or 2 substituents R^(h). In this regard, R^(h) is preferably selectedfrom halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy,C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl and fluorinated C₃-C₆-cycloalkyl. Inthis regard, R^(h) is in particular selected from fluorine, chlorine,methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl andfluorinated cyclopropyl.

In the third embodiment of formulae Ia and Ib, Ar⁴ is e.g. selected fromthe group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl,3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl,1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl,benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl,where the aforementioned radicals are unsubstituted or may carry 1, 2 or3 radicals R^(h) as defined above, which are in particular selected fromthe group consisting of fluorine, chlorine, methyl, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.

A third group of embodiments of the invention relates to compounds ofthe formula I, to their salts, N-oxides, tautomers, hydrates andprodrugs and to the salts of said N-oxides, tautomers, hydrates andprodrugs, where X¹ is C—H and X² is N. In this third group, Y, R¹, R²,R³ and R⁴ are as defined above and preferably have the preferred orparticular or special meanings given above. Amongst these compounds, aparticular group of embodiments is represented by the following formulaIc

where R¹, R², R³ and R⁴ are as defined above.

A fourth group of embodiments of the invention relates to compounds ofthe formula I, to their salts, N-oxides, tautomers, hydrates andprodrugs and to the salts of said N-oxides, tautomers, hydrates andprodrugs, where X¹ is N and X² is N. In this second group, Y, R¹, R², R³and R⁴ are as defined above and preferably have the preferred orparticular or special meanings given above. Amongst these compounds, aparticular group of embodiments is represented by the following formulaId

where R¹, R², R³, R⁴ and R⁵ are as defined above.

In relation to their use as inhibitors of PDE10A, the variables R¹, R²,R³ and R⁴ in formulae Ia, Ib, Ic and Id preferably have the followingmeanings, where these represent, both considered on their own and incombination with at least one other or all, special embodiments of thecompounds of the formula I:

In formulae Ia, Ib, Ic and Id, R¹ is preferably C₂-C₈-alkyl,C₃-C₈-cycloalkyl or C₃-C₈-cycloalkylmethyl, in particularC₃-C₈-cycloalkylmethyl or especially C₂-C₈-alkyl. Particularly, R¹ isalkyl of the formula CHR^(1a)R^(1b), where R^(1a) is selected from thegroup consisting of hydrogen and C₁-C₃-alkyl, in particular methyl,ethyl, n-propyl and where R^(1b) is selected from the group consistingof C₁-C₄-alkyl, in particular methyl, ethyl, n-propyl or n-butyl.Particular examples of R¹ are selected from the group consisting ofethyl, isopropyl, 1-methylpropyl and 1-ethylpropyl.

In formulae Ia, Ib, Ic and Id, R¹ is likewise preferably a moietyZ¹—Ar¹, where Z¹ and Ar¹ are as defined above and where Z¹ is preferably1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atomsmay be replaced by a fluorine atom. According to a specific embodiment,Z¹ is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which isunsubstituted.

In formulae Ia, Ib, Ic and Id, where R¹ is a moiety Z¹—Ar¹, Ar¹ ispreferably selected from the group consisting of C-bound 6-memberedmonocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, andC-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ringmembers and optionally a further heteroatom selected from O, S and N asring member, where monocyclic hetaryl and bicyclic hetaryl may beunsubstituted or may carry 1, 2 or 3 substituents R^(h), in particular0, 1 or 2 substituents R^(h). Ar¹ is in particular selected from thegroup consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogenatoms as ring members and optionally a further heteroatom selected fromO, S and N as ring member and which may be unsubstituted or may carry 1,2 or 3 substituents R^(h), in particular 0, 1 or 2 substituents R^(h) asdefined above. Amongst these, particular preference is given to thosecompounds, where the Ar¹ radical has at least one imino-nitrogen as ringmember, which is located in the position adjacent to carbon atom boundto the group Z¹. Amongst these, particular preference is given to those,where Ar¹ is selected from the group consisting of C-bound, fusedbicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members andoptionally a further heteroatom selected from O, S and N as ring member,where bicyclic hetaryl may be unsubstituted or may carry 1, 2 or 3substituents R^(h), in particular 0, 1 or 2 substituents R^(h). In thisregard, R^(h) is preferably selected from halogen, C₁-C₄-alkyl,C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy, C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl andfluorinated C₃-C₆-cycloalkyl. In this regard, R^(h) is in particularselected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.

In particular embodiments of formulae Ia, Ib, Ic and Id, R² is a radicalof the formula CR²¹R²²R²³, where R²¹, R²² and R²³ are as defined aboveand where R²¹ is in particular different from hydrogen.

In other particular embodiments of formulae Ia, Ib, Ic and Id, R² is aphenyl or 5- or 6-membered hetaryl radical having 1, 2 or 3 heteroatomsas ring members which are selected from O, S and N, where phenyl andmonocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical ordifferent substituents R^(a) as defined above.

In the particular embodiments of formulae Ia, Ib, Ic and Id, where R² isa radical of the formula CR²¹R²²R²³, where R²¹, R²² and R²³ are asdefined above or where R² is a phenyl or 5- or 6-membered hetarylradical having 1, 2 or 3 heteroatoms as ring members which are selectedfrom O, S and N, where phenyl and monocyclic hetaryl are unsubstitutedor may carry 1, 2 or 3 identical or different substituents R^(a) asdefined above, the radical R³ is preferably selected from the groupconsisting of hydrogen and C₁-C₄-alkyl. In these embodiments, R³ is inparticular hydrogen.

In the particular embodiments of formulae Ia, Ib, Ic and Id, where R² isa radical of the formula CR²¹R²²R²³, a particular group of embodimentsrelates to compounds, where the radicals R²¹, R²² and R²³ have thefollowing meanings:

-   -   R²¹ is selected from the group consisting of C₁-C₈-alkyl,        trimethylsilyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl,        C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,        C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinated        C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,        hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)),        (CH₂)_(m)C(O)O—R^(d), (CH₂)_(m)C(O)N(R^(e))(R^(f)) and Z²—Ar²,

-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,    hydroxy-C₁-C₄-alkyl and C₁-C₄-alkyl-N(R^(b))(R^(c)), or

-   R²³ is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl and C₁-C₄-fluoroalkyl;

In the particular embodiments of formulae Ia, Ib, Ic and Id, where R² isa radical of the formula CR²¹R²²R²³, a particular group of embodimentsrelates to compounds, where the radicals R²¹, R²² and R²³ preferablyhave the following meanings, both considered on their own and incombination with at least one other or all:

-   R²¹ is selected from the group consisting of C₂-C₈-alkyl,    trimethylsilyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl and Z²—Ar², where Z² and    Ar², where Z² and Ar² are as defined above and where Z² is    preferably a single bond or CH₂ and Ar² is preferably phenyl,    pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are    unsubstituted or which carry 1, 2 or 3 identical or different    substituents R^(h);-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, in particular hydrogen; and-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In the particular embodiments of formulae Ia, Ib, Ic and Id, where R² isa radical of the formula CR²¹R²²R²³, a particular group of embodimentsrelates to compounds, where the radicals R²¹, R²² and R²³ preferablyhave the following meanings, both considered on their own and incombination with at least one other or all:

-   R²¹ is selected from the group consisting of C₂-C₈-alkyl,    trimethylsilyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,    fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl, and where R²¹ is in    particular C₂-C₄-alkyl;-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, in particular methyl or hydrogen; and-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In the particular embodiments of formulae Ia, Ib, Ic and Id, where R² isa radical of the formula CR²¹R²²R²³, another particular group ofembodiments relates to compounds, where the radicals R²¹, R²² and R²³preferably have the following meanings, both considered on their own andin combination with at least one other or all:

-   R²¹ is a radical Z²—Ar², where Z² and Ar², where Z² and Ar² are as    defined above and where Z² is preferably a single bond or CH₂ and    Ar² is preferably phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl    or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3    identical or different substituents R^(h), particular examples of    R²¹ being 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methylphenyl, 2-, 3-    or 4-methoxyphenyl, 2,3-difluorophenyl, 3,5-difluorophenyl,    3,4-difluorophenyl, thiazol-2-yl, thiazol-4-yl,    1,3,4-thiadiazol-2-yl, 2-(1-morpholinosulfonyl)phenyl,    3-(1-morpholinosulfonyl)phenyl,    2-(4-methylpiperazin-1-ylsulfonyl)phenyl or    3-(4-methylpiperazin-1-ylsulfonyl)phenyl.-   R²² is selected from the group consisting of hydrogen, fluorine,    C₁-C₈-alkyl, in particular methyl or hydrogen; and-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In the particular embodiments of formulae Ia, Ib, Ic and Id, where R² isa radical of the formula CR²¹R²²R²³, a further group of embodimentsrelates to compounds, where the radicals R²¹ and R²² together with thecarbon atom, to which they are bound form a saturated 5-, 6- or7-membered carbocyclic ring, such as cyclopentyl, cyclohexyl orcycloheptyl, especially cyclopentyl, or a saturated 5-, 6- or 7-memberedheterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatomcontaining groups selected from the group of O, N, S, SO and SO₂ as ringmembers, especially 2- or 3-tetrahydrofuryl or 2- or3-tetrahydrothienyl, where the carbocyclic ring and the heterocyclicring may be unsubstituted or may be substituted by 1, 2 or 3 identicalor different substituents R^(g), and where the carbocyclic ring and theheterocyclic ring may carry a fused benzene ring or a fused 5- or6-membered heteroaromatic ring, where the fused rings themselves areunsubstituted or carry 1, 2 or 3 substituents R^(h), and where R^(g),R^(h) and R²³ are as defined above and where R²³ is in particularhydrogen or C₁-C₄-alkyl, such as methyl, or especially hydrogen.

In the particular embodiments of formulae Ia, Ib, Ic and Id, where R² isa radical of the formula CR²¹R²²R²³, a further particular group ofembodiments relates to compounds, where the radicals R²¹, R²² and R²³preferably have the following meanings, both considered on their own andin combination with at least one other or all:

-   R²¹ and R²² together with the carbon atom, to which they are bound    form a saturated 5-, 6- or 7-membered carbocyclic radical, namely a    cyclopentyl, cyclohexyl or cycloheptyl radical or a    3-tetrahydrofuryl or 3-tetrahydrothienyl, where the 5 to 7 membered    carbocyclic ring and the 3-tetrahydrofuryl or 3-tetrahydrothienyl    ring carry a fused benzene ring or a fused 5- or 6-membered    heteroaromatic ring, such as a fused thiophene or pyridine ring,    where the fused rings themselves are unsubstituted or carry 1, 2 or    3 substituents R^(h), and where R²¹ and R²² in particular form a    bicyclic radical selected from the group consisting of 5-indanyl,    6-indanyl, 5,6,7,8-tetrahydronaphthalin-5-yl,    5,6,7,8-tetrahydronaphthalin-6-yl,    6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl,    6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl,    5,6-dihydro-4H-cyclopenta[b]thiophene-4-yl,    6,7-dihydro-5H-[1]-pyrindin-6-yl, 3,4-dihydrobenzofuran-3-yl,    2,3-dihydrobenzothiophen-3-yl or where these bicyclic radicals are    in particular unsubstituted or where the aromatic moiety of these    rings carry 1, 2 or 3 substituents R^(h);-   R²³ is hydrogen or C₁-C₄-alkyl, such as methyl, or especially    hydrogen.

In further particular embodiments of the invention R² and R³ togetherwith the nitrogen atom, to which they are bound form a saturated 4-, 5-,6- or 7-membered heterocyclic ring which, in addition to the nitrogenatom, may have 1 or 2 further heteroatoms or heteroatom containinggroups selected from the group of O, N, S, SO and SO₂ as ring members,e.g. a pyrrolidine, piperidine, morpholine, thiomorpholine or piperazinering, where the heterocyclic ring may be unsubstituted or may besubstituted by 1, 2 or 3 identical or different substituents R³¹, andwhere the heterocyclic ring may carry a fused benzene ring or a fused 5-or 6-membered heteroaromatic ring, such as a thiophene or pyridine ring,where the fused rings themselves are unsubstituted or carry 1, 2 or 3substituents R³², where R³¹ and R³² are as defined defined above.

R³¹ is in particular selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-alkoxy, halogen, phenyl and phenoxy, where the phenylring in thelast two mentioned radicals itself is unsubstituted or carries 1 or 2radicals selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-alkoxy, halogen.

R³² is in particular selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-alkoxy and halogen.

In formulae Ia, Ib, Ic and Id, a particular embodiment relates tocompounds where R⁴ is C₁-C₄-alkyl and especially methyl.

In formulae Ia, Ib, Ic and Id, another particular embodiment relates tocompounds where R⁴ is a radical Z⁴—Ar⁴, where Z⁴ and Ar⁴ are as definedabove and having in particular the preferred, particular or specialmeanings given above. In this embodiment in formulae Ia and Ib R⁵ is inparticular hydrogen, fluorine or in particular C₁-C₄-alkoxy, especiallymethoxy.

In this embodiment of formulae Ia, Ib, Ic and Id, Z⁴ is preferably1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atomsmay be replaced by a fluorine atom. According to a specific embodiment,Z⁴ is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which isunsubstituted.

In this embodiment of formulae Ia, Ib, Ic and Id, Ar⁴ is preferablyselected from the group consisting of C-bound 6-membered monocyclichetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound,fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring membersand optionally a further heteroatom selected from O, S and N as ringmember, where monocyclic hetaryl may be unsubstituted or may carry 1, 2or 3 identical or different substituents R^(k), in particular 0, 1 or 2substituents R^(h) and bicyclic hetaryl may be unsubstituted or maycarry 1 substituent R^(h), and 0, 1, 2 or 3 substituents R^(h), inparticular 0, 1 or 2 substituents R^(h). In this regard, R^(h) ispreferably selected from halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl,C₁-C₄-alkoxy, C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl, and fluorinatedC₃-C₆-cycloalkyl. In this regard, R^(h) is in particular selected fromfluorine, chlorine, methyl, fluoromethyl, difluoromethyl,trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.

In this embodiment of formulae Ia, Ib, Ic and Id, Ar⁴ is in particularselected from the group consisting of fused bicyclic hetaryl, which has1 or 2 nitrogen atoms as ring members and optionally a furtherheteroatom selected from O, S and N as ring member and which may beunsubstituted, or may carry 1 substituent R^(k) and/or may carry 1, 2 or3 substituents R^(h), in particular 0, 1 or 2 substituents R^(h) asdefined above. Amongst these, particular preference is given to thosecompounds, where the Ar⁴ radical has at least one imino-nitrogen as ringmember, which is located in the position adjacent to carbon atom boundto the group Z⁴. Amongst these, particular preference is given to those,where Ar⁴ is selected from the group consisting of C-bound, fusedbicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members andoptionally a further heteroatom selected from O, S and N as ring member,where bicyclic hetaryl may be unsubstituted or may carry 1 substituentR^(k) and/or may carry 1, 2 or 3 substituents R^(h), in particular 0, 1or 2 substituents R^(h). In this regard, R^(h) is preferably selectedfrom halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy,C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl and fluorinated C₃-C₆-cycloalkyl. Inthis regard, R^(h) is in particular selected from fluorine, chlorine,methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl andfluorinated cyclopropyl.

In this embodiment of formulae Ia, Ib, Ic and Id, Ar⁴ is e.g. selectedfrom the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl,3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl,1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl,benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl,where the aforementioned radicals are unsubstituted or may carry 1, 2 or3 radicals R^(h) as defined above, which are in particular selected fromthe group consisting of fluorine, chlorine, methyl, fluoromethyl,difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.

Apart from that, the variables Ar³, Z³, Z⁴, R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), R^(g), R^(h) and R^(k) preferably have, irrespectively oftheir occurrence and with regard to the formulae I, Ia, Ib, Ic and Idand with regard to each of the above mentioned embodiments groups ofembodiments one of the following meanings:

Ar³ is preferably phenyl, which is unsubstituted or substituted by 1, 2or 3 radicals R^(h).

Z³ is preferably a single bond, CH₂ or CH₂CH₂.

Z⁴ is preferably CH₂ or CH₂CH₂.

R^(a) is preferably halogen, in particular fluorine, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy, N(R^(b))(R^(c)),CH₂N(R^(b))(R^(c)), or S(O)₂N(R^(e))(R^(f)),

R^(b) is preferably hydrogen or C₁-C₄-alkyl;

R^(c) is preferably hydrogen or C₁-C₄-alkyl; or

R^(b) and R^(c) together with the nitrogen atom to which they are boundmay also form a saturated N-bound heterocyclic radical, selected fromthe group consisting of pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl and 4-methylpiperazin-1-yl, where the6 aforementioned heterocyclic radicals may carry 1, 2, 3 or 4substituents, selected from methyl and fluorine.

R^(d) is preferably C₁-C₄-alkyl.

R^(e) is preferably hydrogen or C₁-C₄-alkyl;

R^(f) is preferably hydrogen or C₁-C₄-alkyl; or

R^(e) and R^(f) together with the nitrogen atom to which they are boundmay also form a saturated N-bound heterocyclic radical, selected fromthe group consisting of pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl and 4-methylpiperazin-1-yl, where the6 aforementioned heterocyclic radicals may carry 1, 2, 3 or 4substituents, selected from methyl and fluorine.

R^(g) is preferably halogen, in particular fluorine, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-fluoroalkyl or C₁-C₄-fluoroalkoxy.

R^(h) is preferably halogen, in particular fluorine, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-fluoroalkyl, C₁-C₄-fluoroalkoxy, C₃-C₆-cycloalkyl,fluorinated C₃-C₆-cycloalkyl, N(R^(b))(R^(c)), CH₂N(R^(b))(R^(c)) orS(O)₂N(R^(e))(R^(f)). In addition, R^(h) is preferablyC₁-C₂-alkylsulfanyl, C₁-C₂-alkoxy-C₁-C₄-alkoxy, C₃-C₆-cycloalkoxy,C₃-C₆-cycloalkyl-C₁-C₂-alkoxy, phenoxy, 3- to 7-memberedheterocyclyloxy, 3- to 7-membered heterocyclyl-C₁-C₂-alkoxy, whereheterocyclyl in the two last mentioned radicals has 1 or 2 heteroatomsas ring members which are selected from O, S and N, and 5- to 6-memberedhetaryl-C₁-C₂-alkoxy, where hetaryl has 1 or 2 heteroatoms as ringmembers which are selected from O, S and N. R^(h) is in particularselected from halogen, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl, C₁-C₄-alkoxy,C₁-C₂-fluoralkoxy, C₃-C₆-cycloalkyl and fluorinated C₃-C₆-cycloalkyl.R^(h) is especially selected from fluorine, chlorine, methyl,fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinatedcyclopropyl.

R^(k) is preferably halogen, in particular fluorine, C₁-C₄-alkyl,C₁-C₄-alkoxy, C₁-C₄-fluoroalkyl or C₁-C₄-fluoroalkoxy.

Particular embodiments of the invention relates to the compounds offormula I, to the N-oxides, the prodrugs, the hydrates and the tautomersthereof and to the pharmaceutically suitable salts thereof, where thecompounds of the formula I are selected from the group consisting of:

-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid methylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclopropylmethyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid methyl-phenethyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-methoxy-benzyl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (4-methoxy-benzyl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-methoxy-benzyl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid methyl-(3-trifluoromethyl-benzyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid benzyl-(2-dimethylamino-ethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1-benzyl-piperidin-4-yl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid tert-butylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid sec-butylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid isobutyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclopentylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1-methyl-butyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1,1-dimethyl-propyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1,2-dimethyl-propyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2,2-dimethyl-propyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1-ethyl-propyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid ethylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-methyl-butyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid pentylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclohexylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1,3-dimethyl-butyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3,3-dimethyl-butyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-ethyl-butyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid dicyclopropylmethyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-fluoro-ethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclohexylmethyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1-phenyl-ethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-fluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3-fluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 4-fluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2,3-difluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2,4-difluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2,6-difluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3,4-difluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2,2,2-trifluoro-ethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3,5-difluoro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid phenethyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid [1-(4-fluoro-phenyl)-ethyl]-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-1-ylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-2-ylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid [1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide,-   4-(azetidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclopropylamide,-   2-ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin-1-one,-   2-ethyl-4-(3-fluoro-pyrrolidine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinolin-1-one,-   4-(3,3-difluoro-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   4-(3-dimethylamino-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one,-   4-(1,3-dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   4-(4,4-difluoro-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid isopropylamide,-   2-ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one,-   4-(4-dimethylamino-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one,-   4-(4-cyclopropylmethyl-piperazine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-2H-isoquinolin-1-one,-   4-[4-(2-dimethylamino-ethyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   4-([1,4′]bipiperidinyl-1′-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   4-[4-(3-dimethylamino-propyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid propylamide,-   2-ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid dimethylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid ethyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid isopropyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid diethylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid methyl-propyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid ethyl-isopropyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid tert-butyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid isobutyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid ethyl-propyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-dimethylamino-ethyl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid ethyl-(2-methoxy-ethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclopentyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butyl-ethyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid methyl-pentyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid diisopropylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid isopropyl-propyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclobutylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid dipropylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-dimethylamino-propyl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclohexyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclopropylmethyl-propyl-amide-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid diisobutylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid benzyl-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-fluoro-benzyl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (4-fluoro-benzyl)-methyl-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-fluoro-benzyl)-methyl-amide,-   2-tert-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-sec-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-cyclopropylmethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-(2-dimethylamino-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   6,7-dimethoxy-1-oxo-2-(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide-   6,7-dimethoxy-1-oxo-2-(2-pyrrolidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-(2-fluoro-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-(2,4-difluoro-benzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   6,7-dimethoxy-1-oxo-2-(2-piperidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   6,7-dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   6,7-dimethoxy-2-(2-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   6,7-dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   6,7-dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   6,7-dimethoxy-2-(2-methoxy-ethyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid butylamide,-   2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid    butylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-1-ylamide,-   2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (R)-indan-1-ylamide,-   2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid indan-1-ylamide,-   2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid butylamide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-1-ylamide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (1,2,3,4-tetrahydro-naphthalen-2-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (4-bromo-indan-1-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (5-bromo-indan-1-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid 2-dimethylaminomethyl-benzylamide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (6,7-dihydro-5H-[1]pyrindin-7-yl)-amide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid 3-dimethylaminomethyl-benzylamide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid 4-dimethylaminomethyl-benzylamide,-   7-methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic    acid butylamide,-   7-methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-1-ylamide,-   3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (S)-indan-1-ylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-dimethylaminomethyl-benzylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3,5-difluoro-benzylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3,4-difluoro-benzylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid cyclohexylmethyl-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (R)-indan-1-ylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (S)-indan-1-ylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid pyridin-3-ylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (pyrimidin-4-ylmethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-methoxy-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (4-morpholin-4-yl-phenyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3-chloro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (pyridin-4-ylmethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid o-tolylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid m-tolylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-methoxy-phenyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-methoxy-phenyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (pyridin-3-ylmethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (pyridin-2-ylmethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-dimethylamino-propyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid phenylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 4-methoxy-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3-methyl-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-methyl-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-methoxy-ethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (4-fluoro-phenyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (4-methoxy-phenyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid p-tolylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-fluoro-phenyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-fluoro-phenyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 4-methyl-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-chloro-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid pyridin-4-ylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (6-methyl-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-morpholin-4-ylmethyl-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (5-chloro-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (6-chloro-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (6-fluoro-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (4-fluoro-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (4-methyl-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (5-methyl-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (6-methoxy-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (5-fluoro-indan-1-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-diethylaminomethyl-benzylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-pyrrolidin-1-ylmethyl-benzylamide,-   2-ethyl-6,7-dimethoxy-4-(4-methyl-piperidine-1-carbonyl)-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (tetrahydro-furan-2-ylmethyl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-methoxy-propyl)-amide,-   4-(3,5-dimethyl-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-ethyl-4-(4-ethyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-isobutyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinolin-1-one,-   2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2-dimethylamino-ethyl)-amide,-   2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid butyl-methyl-amide,-   1(2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonyl)-aminol-acetic    acid methyl ester,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (3-isopropoxy-propyl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2,3-dihydro-benzofuran-3-yl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   2-cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-1-ylamide,-   2-sec-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-1-ylamide,-   2-isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid indan-1-ylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-piperidine-1-carbonyl)-2H-isoquinolin-1-one,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine-1-carbonyl)-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (S)indan-1-ylamide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (R)indan-1-ylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-piperazine-1-carbonyl]-2H-isoquinolin-1-one,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperazine-1-carbonyl]-2H-isoquinolin-1-one,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid ([1,3,4]thiadiazol-2-ylmethyl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-(morpholine-4-sulfonyl)-benzylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (thiazol-4-ylmethyl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidine-1-carbonyl]-2H-isoquinolin-1-one,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (S)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (R)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (thiophen-3-ylmethyl)-amide,-   4-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7-dimethoxy-2H-isoquinolin-1-one,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3-(4-chloro-benzenesulfonylamino)-benzylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid (S)-indan-1-ylamide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid 2-(morpholine-4-sulfonyl)-benzylamide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid 3,5-difluoro-benzylamide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid 4-methyl-benzylamide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid cyclohexylmethyl-amide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid butylamide,-   2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid (2,3-dihydro-benzofuran-3-yl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (thiazol-2-ylmethyl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic    acid (thiophen-2-ylmethyl)-amide,-   2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic    acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,-   3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (2,3-dihydro-benzofuran-3-yl)-amide,-   3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid indan-1-ylamide,-   3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic    acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,-   2-(1-ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin-1-one,    and-   2-ethyl-6,7-dimethoxy-N-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide.

Particular embodiments of the invention also relates to the compounds offormula I, to the N-oxides, the prodrugs, the hydrates and the tautomersthereof and to the pharmaceutically suitable salts thereof, where thecompounds of the formula I are selected from the group consisting of:

-   6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-((3,5-dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((3-methylisoxazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-((2,5-dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   (R)—N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   (S)—N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((4-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((5-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroiso-quinoline-4-carboxamide,-   6,7-dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-((2-ethylthiazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((4-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((3-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((5-methyloxazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-(4-methylbenzyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-((5-cyanofuran-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-(4-chloro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-((5-ethylthiophen-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((3-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((2-methylfuran-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   6,7-dimethoxy-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide,-   N-[(3,4-dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-[(2-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-[[2-(dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide,-   N-[(2-tert-butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-[[2-(1,1-dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-[(2,3-difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-[(3-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-1-oxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline-4-carboxamide,-   N-[(2,4-dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide,-   N-[[2-(2-ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-[[2-(cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[[2-(2-methoxy-1-methyl-ethoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide,-   N-[[2-(cyclohexoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-[[2-(cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3-ylmethoxy)phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   N-(2-ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   N-(2-sec-butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-1-oxo-N-(2,4,5-trimethylbenzyl)-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2-yl)methoxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-1-oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-1-oxo-N-[[4-(trifluoromethyl)phenyl]methyl]isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-1-oxo-N-[(1S)-1-(p-tolyl)ethyl]isoquinoline-4-carboxamide,-   2-ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-1-oxo-N-[(1R)-1-(p-tolyl)ethyl]isoquinoline-4-carboxamide,-   N-[[4-(difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl]-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl]-1-oxo-isoquinoline-4-carboxamide,-   N-[(4-cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide,-   N-indan-1-yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide,-   N-butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide,-   2-ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide,-   N-butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quino    1yl)ethyl]isoquinoline-4-carboxamide, and-   N-indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quino    1yl)ethyl]iso    quinoline-4-carboxamide.

In particular embodiments, the compounds of the present invention aredistinct from the group of the following compounds:

-   1-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]-(3-ethoxycarbonyl)piperidine,-   1-[(2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)-carbonyl]-(3-ethoxycarbonyl)piperidine,-   2-{[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]amino}-benzoic    acid ethyl ester,-   N-cycloheptyl-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3-ethoxypropyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3-(1-methylethoxy)propyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3-(1-methylethoxy)propyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3-ethoxypropyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-[3-(4-methyl-1-piperidinyl)propyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-[3-(2-ethyl-1-piperidinyl)propyl]-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3-acetylaminophenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N,N-diethyl-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(5-methyl-2-furanylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(5-methyl-2-furanylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(2-furanylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(tetrahydro-2-furanylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(2-pyridylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3-pyridylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(1,3-benzodioxol-5-ylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(1,3-benzodioxol-5-ylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-ethyl-N-(2-methylphenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-ethyl-N-(2-ethylphenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3,4-dimethoxyphenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   N-(3-chlorophenyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline    carboxamide,-   4-[(4-propyl-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-4-isoquinolin-1-one,-   4-[(4-cyclohexyl-1-piperazinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-4-isoquinolin-1-one,-   4-[(4-cyclohexyl-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-4-isoquinolin-1-one,-   4-[(4-(2-pyridyl)-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-4-isoquinolin-1-one,-   4-[(4-(3-chlorophenyl)-1-piperazinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-4-isoquinolin-1-one,-   4-{[4-(2-furanylcarbonyl)-1-piperazinyl]carbonyl}-2-ethyl-1,2-dihydro-6,7-dimethoxy-4-isoquinolin-1-one,-   4-[(3,4-dihydro-1(2H)quinolinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-4-isoquinolin-1-one,-   N-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]glycine    methyl ester,-   N-[(2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]glycine    methyl ester,-   N-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]glycine    ethyl ester,    the pharmaceutically acceptable salts thereof, the N-oxides thereof,    the prodrugs thereof, the hydrates thereof, the tautomers the and    the pharmaceutically acceptable salts of said N-oxides, prodrugs,    tautomers or hydrates.

The compounds of the invention of the general formulae I, Ia, Ib, Ic andId and the starting materials used to prepare them can be prepared inanalogy to known processes of organic chemistry as are described instandard works of organic chemistry, e.g. Houben-Weyl, “Methoden derOrganischen Chemie”, Thieme-Verlag, Stuttgart, Jerry March “AdvancedOrganic Chemistry”, 5^(th) edition, Wiley & Sons and the literaturecited therein, and R. Larock, “Comprehensive Organic Transformations”,2^(nd) edition, Weinheim, 1999 and the literature cited therein. Thecompounds of the invention of the general formula I are advantageouslyprepared by the methods described below and/or in the experimentalsection.

Compounds of the formula I, wherein Y is oxygen, can be prepared e.g. byreacting a compound of the formula II with an amine of the formula III,as depicted in scheme 1.

where X¹, X², R¹, R², R³ and R⁴ are as defined above. Q is a suitableleaving group such as chlorine, bromine or OH or a radical of anactivated ester such as para-nitrophenoxy, pentafluorophenoxy,N-hydroxysuccinimide or hydroxybenzotriazol-1-yl. suitable reactionconditions have been described e.g. in Houben-Weyl: “Methoden der organ.Chemie” [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart,New York 1985, Volume E5, pp. 941-1045).

The reaction of II with III may be performed in the presence of a base.Suitable base include but are not limited to

If Q is OH, the reaction may be performed in the presence of a couplingagent.

Suitable coupling agents are, for example:

-   -   coupling agents based on carbodiimides, for example        N,N′-dicyclohexylcarbodiimide [J. C. Sheehan, G. P. Hess, J. Am.        Chem. Soc. 1955, 77, 1067],        N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide;    -   coupling agents which form mixed anhydrides with carbonic        esters, for example        2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline [B. Belleau, G.        Malek, J. Amer. Chem. Soc. 1968, 90, 1651],        2-isobutyloxy-1-isobutyloxycarbonyl-1,2-dihydroquinoline [Y.        Kiso, H. Yajima, J. Chem. Soc., Chem. Commun 1972, 942];    -   coupling agents based on phosphonium salts, for example        (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexafluorophosphate [B. Castro, J. R. Domoy, G. Evin, C. Selve,        Tetrahedron Lett. 1975, 14, 1219],        (benzotriazol-1-yl-oxy)tripyrrolidinophosphonium        hexafluorophosphate [J. Coste et al., Tetrahedron Lett. 1990,        31, 205];    -   coupling agents based on uronium salts or having a guanidinium        N-oxide structure, for example        N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium        hexafluorophosphate [R. Knorr, A. Trzeciak, W. Bannwarth, D.        Gillessen, Tetrahedron Lett. 1989, 30, 1927],        N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium        tetrafluoroborate, (benzotriazol-1-yloxy)dipiperidinocarbenium        hexafluorophosphate [S. Chen, J. Xu, Tetrahedron Lett. 1992, 33,        647];    -   coupling agents which form acid chlorides, for example        bis-(2-oxo-oxazolidinyl)phosphinic chloride [J. Diago-Mesequer,        Synthesis 1980, 547].

Apart from that, compounds of the formula I and likewise compounds ofthe formula II, where Q is S can be prepared by successively reactingcompounds of the formulae I and II, where Q is O with a suitablesulfurizing agent, such as Lawenson's reagent or P₂S₅.

The N-oxides of compound I may be prepared from the compounds of formulaI according to conventional oxidation methods, for example by treatingsaid compounds with an organic peracid; such as metachloroperbenzoicacid or 3-chloroperbenzoic acid [Journal of Medicinal Chemistry 38(11),1892-1903 (1995), WO 03/64572]; or with inorganic oxidizing agents; suchas hydrogen peroxide [cf. Journal of Heterocyclic Chemistry 18 (7),1305-1308 (1981)] or oxone [cf. Journal of the American Chemical Society123(25), 5962-5973 (2001)]. The oxidation may lead to pure mono-N-oxidesor to a mixture of different N-oxides, which can be separated byconventional methods; such as chromatography.

The compounds of the formulae II and III are well known in the art orcan be prepared by anology to well established reactions of organicsynthetic chemistry or by analogy to the methods as described instandard works of organic chemistry, e.g. Houben-Weyl, “Methoden derOrganischen Chemie”, Thieme-Verlag, Stuttgart, Jerry March “AdvancedOrganic Chemistry”, 5^(th) edition, Wiley & Sons and the literaturecited therein, and R. Larock, “Comprehensive Organic Transformations”,2^(nd) edition, Weinheim, 1999 and the literature cited therein.

The compounds of the formula II, where Q is OH can be easily transformedinto compounds of the formula II, where Q is halogen, in particularchlorine by a suitable chlorination agent such as thionylchloride oroxalyl chloride.

Compounds of the formula II, where X² is C—R⁵, where R⁵ is a radicalO—Z⁵—Ar⁵ can be prepared e.g. by reacting compounds of the formula II,where X² is C—OH with a compound of formula HO—Z⁵—Ar⁵ (formula IV) interms of a Mitsunobu reaction, i.e. in the presence of dialkylazodicarboxylate and triphenylphosphine (for suitable reactionconditions see e.g. A. J. Reynolds et al. Curr. Org. Chem. 13(16) (2009)pp. 1610-16-32; K. C. Swamy et al., Chem. Rev. 109(6) (2009), pp.2551-2651; D. L. Hughes, Organic Preparations and ProceduresInternational 28(2)(1996), pp. 127-164.

Compounds of the formula II, where X¹ is CH and Q is OH (compounds Ha),can be prepared e.g. according to the following reaction scheme 2:

In scheme 2, X², R¹ and R⁴ are as defined above. R is C₁-C₄-alkyl, inparticular methyl.

Step a) is performed by reacting a compound of the formula V withdimethoxymethyl dimethylamine (also termed dimethylformamidedimethylacetal). Thereby the compound of formula VI is obtained, whichcan be cyclised in step b) to the compound of formula II, where Q ismethoxy, by reaction with a primary amine of the formula H₂N—R¹(compound VII). Subsequent hydrolysis of the primarily obtained ester instep c) yields the compound of the formula II, where X¹ is CH and Q isOH.

Compounds of the formula II, where X¹ is N and Q is OH (compounds III)),can be prepared e.g. according to the following reaction scheme 3:

In scheme 3, X², R¹ and R⁴ are as defined above.

Step d) is performed by reacting a compound of the formula VIII with anexcess of a suitable oxidising agent in the presence of water, e.g.aqueous potassium permanganate. Thereby the compound of formula IX isobtained, which can be cyclised in step e) to a phthalazinone orphthalazinone analogue by reaction with hydrazine. Subsequent alkylationwith an alkylating agent of formula R¹-Q′ in step f) yields the compoundof the formula II, where X¹ is CH and Q is OH.

The reactions are usually performed in an organic solvent, includingaprotic organic solvent, e.g. substituted amides, lactames and ureas;such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetramethyl urea, cyclic ethers; such as dioxane, tetrahydrofurane,halogenated hydrocarbons; such as dichloromethane, and mixtures thereofas well as mixtures thereof with C₁-C₆-alkanols and/or water.

The reactions described above will be usually performed at temperaturesranging from −10° C. to 100° C., depending on the reactivity of the usedcompounds.

The reaction mixtures are worked up in a conventional way, e.g. bymixing with water, separating the phases and, where appropriate,purifying the crude products by chromatography. The intermediates andfinal products in some cases result in the form of colorless or palebrownish, viscous oils which are freed of volatiles or purified underreduced pressure and at moderately elevated temperature. If theintermediates and final products are obtained as solids, thepurification can also take place by recrystallization or digestion.

Due to their capability of inhibiting PDE10A at low concentrations, thecompounds of the formula I, their N-oxides, their hydrates, theirtautomers and their prodrugs and the pharmaceutically acceptable saltsthereof, are particularly suitable for treating disorders or conditions,which can be treated by inhibition of phosphodiesterase type 10A. Theterms “treating” and “treatment” in terms of the present invention haveto be understood to include both curative treatment of the cause of adisease or disorder, the treatment of the symptoms associated with adisease or disorder, i.e. controlling the disease or disorder orameliorating the conditions or symptoms associated with a disease ordisorder, and prophylactic treatment, i.e. a treatment for reducing therisk of a disease or disorder.

Neurological and psychiatric disorders or conditions which can betreated by inhibition of PDE10A, including curative treatment, controlor amelioration and prophylaxis, include CNS disorders, in particularschizophrenia, depression, bipolar disorders, cognitive dysfunctionsassociated with schizophrenia, cognitive dysfunctions associated withAlzheimer's disease, Huntington's disease (Huntington chorea), anxietyand substance-related disorders, especially substance use disorder,substance tolerance conditions associated with substance withdrawal.Disorders or conditions which can be treated by inhibition of PDE10A,including curative treatment, control or amelioration and prophylaxis,also include treatment of diet induced obesity.

Thus, the invention relates to the use of compounds of formula I, theirN-oxides, their hydrates, their tautomers and their prodrugs and thepharmaceutically acceptable salts thereof, for treatment of disorders orconditions, which can be treated by inhibition of phosphodiesterase type10A, i.e. the invention relates to the use of such compounds forcurative treatment of such a disease or disorder, controlling such adisease or disorder, ameliorating the symptoms associated with such adisease or disorder and reducing the risk for such a disease ordisorder.

The present invention also relates to a method for the treatment of amedical disorder, selected from neurological and psychiatric disorderswhich can be treated by inhibition of phosphodiesterase type 10A, saidmethod comprising administering an effective amount of at least onecompound, selected from the group of compounds of formula I, theirN-oxides, their hydrates, their tautomers, their prodrugs and thepharmaceutically acceptable salts thereof, to a mammal in need thereof.

The present invention in particular relates to:

-   -   a method for treating, controlling, ameliorating or reducing the        risk of schizophrenia in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of cognitive disturbances associated with schizophrenia in        a mammalian; a method for treating, controlling, ameliorating or        reducing the risk of depression in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of bipolar disorders in a mammalian;    -   a method for treating or ameliorating the symptoms associated        with substance use disorders in a mammalian;    -   a method for treating or ameliorating the symptoms associated        with diet-induced obesity in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of cognitive disturbances associated with Alzheimer's        disease in a mammalian; a method for treating, controlling,        ameliorating or reducing the risk of behavioral symptoms in        Alzheimer's disease;    -   a method for treating, controlling, ameliorating or reducing the        risk of anxiety in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of Huntington's disease in a mammalian;

which methods comprising administering an effective amount of at leastone compound, selected from the group of compounds of formula I, theirN-oxides, their hydrates, their tautomers, their prodrugs and thepharmaceutically acceptable salts thereof, to a mammal in need thereof.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition of PDE10Ais desired. The terms “effective amount” and “therapeutically effectiveamount” mean the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes, wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe disorders described herein, but does not necessarily indicate atotal elimination of all disorder symptoms, as well as the prophylactictherapy of the mentioned conditions, particularly in a patient who ispredisposed to such disease or disorder. The term “composition” as usedherein is intended to encompass a product comprising the specifiedingredients in the specified amounts, as well as any product whichresults, directly or indirectly, from combination of the specifiedingredients in the specified amounts. Such term in relation topharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s) thatmake up the carrier, as well as any product which results, directly orindirectly, from combination, complexation or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of and or “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individual in need of treatment.

A preferred embodiment of the present invention provides a method fortreating schizophrenia, comprising: administering to a patient in needthereof an effective amount of at least one compound, selected from thegroup of compounds of formula I, their N-oxides, their hydrates, theirtautomers, their prodrugs and the pharmaceutically acceptable saltsthereof.

In another preferred embodiment, the present invention provides a methodfor treating cognitive disturbances associated with schizophrenia,comprising: administering to a patient in need thereof an effectiveamount of at least one compound, selected from the group of compounds offormula I, their N-oxides, their hydrates, their tautomers, theirprodrugs and the pharmaceutically acceptable salts thereof.

At present, the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool including schizophreniaand other psychotic disorders. These include: disorders having psychoticsymptoms as the defining feature. The term psychotic refers todelusions, prominent hallucinations, disorganized speech, disorganizedor catatonic behavior. The disorder includes: paranoid, disorganized,catatonic, undifferentiated, and residual schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition, substance-induced psychoticdisorder, and psychotic disorder not otherwise specified. The skilledartisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, and particular schizophrenia, and that these systems evolvewith medical scientific progress. Thus, the term “schizophrenia” isintended to include like disorders that are described in otherdiagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating substance-related disorders, comprising: administering to apatient in need thereof an effective amount of at least one compound,selected from the group of compounds of formula I, their N-oxides, theirhydrates, their tautomers, their prodrugs and the pharmaceuticallyacceptable salts thereof.

In another preferred embodiment, the present invention provides a methodfor treating anxiety, comprising: administering to a patient in needthereof an effective amount of at least one compound, selected from thegroup of compounds of formula I, their N-oxides, their hydrates, theirtautomers, their prodrugs and the pharmaceutically acceptable saltsthereof. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding anxiety and related disorders. These include: panic disorderwith or without agoraphobia, agoraphobia without history of panicdisorder, specific phobia, social phobia, obsessive-compulsive disorder,post-traumatic stress disorder, acute stress disorder, generalizedanxiety disorder, anxiety disorder due to a general medical condition,substance-induced anxiety disorder and anxiety disorder not otherwisespecified. As used herein the term “anxiety” includes treatment of thoseanxiety disorders and related disorder as described in the DSM-IV. Theskilled artisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, and particular anxiety, and that these systems evolve withmedical scientific progress. Thus, the term “anxiety” is intended toinclude like disorders that are described in other diagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating depression, comprising: administering to a patient in needthereof an effective amount of at least one compound, selected from thegroup of compounds of formula I, their N-oxides, their hydrates, theirtautomers, their prodrugs and the pharmaceutically acceptable saltsthereof. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolincluding depression and related disorders. Depressive disordersinclude, for example, single episodic or recurrent major depressivedisorders, and dysthymic disorders, depressive neurosis, and neuroticdepression; melancholic depression including anorexia, weight loss,insomnia and early morning waking, and psychomotor retardation; atypicaldepression (or reactive depression) including increased appetite,hypersomnia, psychomotor agitation or irritability, anxiety and phobias;seasonal affective disorder; or bipolar disorders or manic depression,for example, bipolar I disorder, bipolar II disorder and cyclothymicdisorder. As used herein the term “depression” includes treatment ofthose depression disorders and related disorder as described in theDSM-1V.

In another preferred embodiment, the present invention provides a methodfor treating substance-related disorders, especially substancedependence, substance abuse, substance tolerance, and substancewithdrawal, comprising: administering to a patient in need thereof aneffective amount at least one compound, selected from the group ofcompounds of formula I, their N-oxides, their hydrates, their tautomers,their prodrugs and the pharmaceutically acceptable salts thereof. Atpresent, the fourth edition of the Diagnostic and Statistical Manual ofMental Disorders (DSM-IV) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool including disordersrelated to taking a drug of abuse (including alcohol), to the sideeffects of a medication, and to toxin exposure. Substances includealcohol, amphetamine and similarly acting sympathomimetics, caffeine,cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids,phencyclidine (PCP) or similarly acting arylcyclohexylamines, andsedatives, hypnotics, or anxiolytics. Also, polysubstance dependence andother unknown substance-related disorders are included. The skilledartisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, and particular substance-related disorders, and that thesesystems evolve with medical scientific progress. Thus, the term“substance-related disorder” is intended to include like disorders thatare described in other diagnostic sources.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require inhibition of PDE10A an appropriatedosage level will generally be about 0.01 to 500 mg per kg patient bodyweight per day which can be administered in single or multiple doses.Preferably, the dosage level will be about 0.1 to about 250 mg/kg perday; more preferably about 0.5 to about 100 mg/kg per day. A suitabledosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range thedosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oraladministration, the compositions are preferably provided in the form oftablets containing 1.0 to 1000 milligrams of the active ingredient,particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0,200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 4 times per day, preferably once ortwice per day. When treating, preventing, controlling, ameliorating, orreducing the risk of neurological and psychiatric disorders or otherdiseases for which compounds of the present invention are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.1milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. For most large mammals, thetotal daily dosage is from about 1.0 milligrams to about 1000milligrams, preferably from about 1 milligram to about 50 milligrams, inthe case of a 70 kg adult human, the total daily dose will generally befrom about 7 milligrams to about 350 milligrams. This dosage regimen maybe adjusted to provide the optimal therapeutic response. It will beunderstood, however, that the specific dose level and frequency ofdosage for any particular patient may be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular condition, and the host undergoing therapy.

The compounds of the present invention may be administered byconventional routes of administration, including parenteral (e.g.,intramuscular, intrapentoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), oral, byinhalation spray, nasal, vaginal, rectal, sublingual, or topical routesof administration.

The compounds according to the present invention are further useful in amethod for the prevention, treatment, control, amelioration, orreduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of Formula I. When a compound of formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of formula I. The abovecombinations include combinations of a compound of the present inventionnot only with one other active compound, but also with two or more otheractive compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The present invention also relates to pharmaceutical compositions (i.e.medicaments) which comprise at least one compound of the presentinvention and, where appropriate, one or more suitable excipients.

These excipients/drug carriers are chosen according to thepharmaceutical form and the desired mode of administration.

The compounds of the present invention can be used to manufacturepharmaceutical compositions for parenteral (e.g., intramuscular,intrapentoneal, intravenous, ICV, intracisternal injection or infusion,subcutaneous injection, or implant), oral, sublingual, intratracheal,intranasal, topical, transdermal, vaginal or rectal administration, andbe administered to animals or humans in unit dose forms, mixed withconventional pharmaceutical carriers, for the prophylaxis or treatmentof the above impairments or diseases.

In the pharmaceutical compositions, the at least one compound of thepresent invention may be formulated alone or together with furtheractive compounds, in suitable dosage unit formulations containingconventional excipients, which generally are non-toxic and/orpharmaceutically acceptable. Carriers or excipients can be solid,semisolid or liquid materials which serve as vehicles, carriers ormedium for the active compound. Suitable excipients are listed in thespecialist medicinal monographs. In addition, the formulations cancomprise pharmaceutically acceptable carriers or customary auxiliarysubstances, such as glidants; wetting agents; emulsifying and suspendingagents; preservatives; antioxidants; antiirritants; chelating agents;coating auxiliaries; emulsion stabilizers; film formers; gel formers;odor masking agents; taste corrigents; resin; hydrocolloids; solvents;solubilizers; neutralizing agents; diffusion accelerators; pigments;quaternary ammonium compounds; refatting and overfatting agents; rawmaterials for ointments, creams or oils; silicone derivatives; spreadingauxiliaries; stabilizers; sterilants; suppository bases; tabletauxiliaries, such as binders, fillers, glidants, disintegrants orcoatings; propellants; drying agents; opacifiers; thickeners; waxes;plasticizers and white mineral oils. A formulation in this regard isbased on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe ftir Pharmazie, Kosmetik and angrenzendeGebiete [Encyclopedia of auxiliary substances for pharmacy, cosmeticsand related fields], 4^(th) edition, Aulendorf:ECV-Editio-Kantor-Verlag, 1996.

Suitable unit dose forms include forms for oral administration, such astablets, gelatin capsules, powders, granules and solutions orsuspensions for oral intake, forms for sublingual, buccal, intratrachealor intranasal administration, aerosols, implants, forms of subcutaneous,intramuscular or intravenous administration and forms of rectaladministration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

If a solid composition is prepared in the form of tablets, the mainingredient is mixed with a pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets may be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display aprolonged or delayed activity and in order to release a predeterminedamount of the active basic ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and taking up the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may comprise active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloring.

The water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agentssuch as polyvinylpyrrolidones, and sweeteners or taste improvers.

Rectal administration is achieved by the use of suppositories which areprepared with binders which melt at the rectal temperature, for examplecocobutter or polyethylene glycols. Parenteral administration iseffected by using aqueous suspensions, isotonic salt solutions orsterile and injectable solutions which comprise pharmacologicallysuitable dispersants and/or wetting agents, for example propylene glycolor polyethylene glycol.

The active basic ingredient may also be formulated as microcapsules orliposomes/centrosomes, if suitable with one or more carriers oradditives.

In addition to the compounds of the general formula I, their prodrugs,their N-oxides, their tautomers, their hydrates or theirpharmaceutically suitable salts, the compositions of the invention maycomprise further active basic ingredients which may be beneficial forthe treatment of the impairments or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active basic ingredients arepresent together, where at least one thereof is a compound of theinvention.

When producing the pharmaceutical compositions, the compounds accordingto the invention are optionally mixed or diluted with one or morecarriers.

The following examples are intended for further illustration of thepresent invention.

EXAMPLES

The compounds were either characterized via proton-NMR ind₆-dimethylsulfoxide or d-chloroform on a 400 MHz or 500 MHz NMRinstrument (Bruker AVANCE), or by mass spectrometry, generally recordedvia HPLC-MS in a fast gradient on C18-material (electrospray-ionisation(ESI) mode), or melting point.

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (δ) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H-NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet(m).

ABBREVIATIONS

-   DMSO dimethylsulfoxide-   DMF dimethylformamide-   DMA dimethylacetamide-   MeOH methanol-   EtOH ethanol-   AcOH acetic acid-   EtOAc ethyl acetate-   DCM dichloromethane-   DIPEA or DIEA diisoproylethyl amine-   TFA trifluoroacetic acid-   HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate methanaminium-   PS-TFP 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene-   r.t. room temperature-   RT retention time-   Prep-TLC preperative thin layer chromatography

I. PREPARATION EXAMPLES Example 12-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide 1.1 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid dimethylester

To rapidly stirred cold (0° C.) dimethyl malonate (20 mL) was addedsodium (423 mg, 18.38 mmol) in portions. After the addition wascomplete, the mixture was stirred until the sodium disappeared and themixture turned to a white colloidal suspension. Cuprous bromide (110 mg,0.7660 mmol) and 2-bromo-4, 5-dimethoxybenzoic acid (2.00 g, 7.760 mmol)were added. The mixture was heated at 70° C. for 6 h. The reactionmixture was dissolved in water and extracted with toluene and EtOAc. Theaqueous layer was acidified with HCl (2 N). The mixture was thenextracted with EtOAc, dried over Na₂SO₄, filtered and concentrated invacuo to give the product as an oil. After standing overnight the titlecompound was obtained as a solid (1.3 g, yield 54%).

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.58 (s, 1H, ArH), 6.92 (s, 1H, ArH),5.98 (s, 1H, CH), 3.87 (s, 3H, CH₃), 3.72 (s, 3H, CH₃).

LCMS (ESI+): m/z 313 (M+H)⁺, RT: 1.29 min.

1.2 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid

A solution of sodium hydroxide (1.92 g, 48.03 mmol) in water (20 mL) wasadded over 30 min to a solution of the compound obtained in step 1.1(3.0 g, 9.6 mmol) in methanol (30 mL) at room temperature. After stirredfor 3 h, methanol was removed under reduced pressure, and the contentswere acidified with HCl (conc.) at r.t. to pH 3. The resulting whiteaqueous suspension was extracted twice with EtOAc (100 mL), and theorganic layer was dried over Na₂SO₄. After filtration and concentrationin vacuo the title product was obtained as a white solid (1.8 g, 67%).

¹H NMR (DMSO-d₆/TMS, 400 MHz) δ: 12.67 (s, 3H, COOH), 7.48 (s, 1H, ArH),6.88 (s, 1H, ArH), 5.76 (s, 1H, CH), 3.81 (s, 3H, CH₃), 3.78 (s, 3H,CH₃).

LCMS (ESI+): m/z 307 (M+Na)⁺, RT: 0.71 min.

1.3 2-Carboxymethyl-4,5-dimethoxy-benzoic acid

The product obtained in step 1.2 (1.8 g, 6.4 mmol) was suspended intoluene (40 mL), and the suspension was heated at 105° C. overnight. Theprecipitates were removed by filtration. The filtrate was concentratedto afford the title product as a white solid. This was used in the nextstep without further purification.

LCMS (ESI+): m/z 263 (M+Na)⁺, RT: 1.32 min.

1.4 4,5-Dimethoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester

Thionyl chloride (0.74 g, 6.245 mmol) was added dropwise to a solutionof the compound obtained in step 1.3 (0.50 g, 2.082 mmol) in methanol (5mL) at ambient temperature. After the addition was completed, themixture was then heated at 65° C. overnight. The solvent wasconcentrated in vacuo. The concentrate was diluted with EtOAc (50 mL)and washed with saturated aqueous NaHCO₃ (10 mL), water (10 mL) andbrine (10 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel column (petrolether:EtOAc=5:1) to afford the title product as a white solid (0.5 g,60%).

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.56 (s, 1H, ArH), 6.72 (s, 1H, ArH),3.97 (s, 2H, CH₂), 3.93 (s, 3H, CH₃), 3.92 (s, 3H, CH₃), 3.86 (s, 3H,CH₃), 3.71 (s, 3H, CH₃).

LCMS (ESI+): m/z 269 (M+H)⁺, RT: 1.69 min.

1.5 2-(2-Dimethylamino-1-methoxycarbonylvinyl)-4,5-dimethoxy-benzoicacid methyl ester

A mixture of the compound obtained in step 1.4 (2.05 g, 7.641 mmol) inDMF-DMA (20 mL) was heated at 90° C. overnight. The reaction mixture wasconcentrated in vacuo. The residue was diluted with EtOAc and washedwith brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified on silica gel column(petrol ether:EtOAc=3:1) to afford the title product as a white solid(0.78 g, 32%).

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.43 (s, 1H, ArH), 7.38 (s, 1H, ArH),6.59 (s, 1H, CH), 3.86 (s, 3H, CH₃), 3.84 (s, 3H, CH₃), 3.73 (s, 3H,CH₃), 3.53 (s, 3H, CH₃), 2.61 (s, 6H, N(CH₃)₂).

LCMS (ESI+): m/z 265 (M+H)⁺, RT: 1.52 min.

1.6 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid methyl ester

A mixture of the compound obtained in step 1.5 (80 mg, 0.2474 mmol),ethylamine hydrochloride (61 mg, 0.7423 mmol) and DIPEA (1 mL) inmethanol (5 mL) was heated at reflux overnight. The solvent was removedunder reduced pressure. The residue was diluted with EtOAc (50 mL) andwashed with HCl (2 N, 10 mL) and brine (10 ML). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle product as a white solid (68 mg, yield 95%). The product was pureenough to be used in the next step without further purification.

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 8.40 (s, 1H, ArH), 8.13 (s, 1H, ArH),7.83 (s, 1H, ArH), 4.12 (q, J=6.8 Hz, J=7.2 Hz, 2H, CH₂), 4.05 (s, 3H,CH₃), 4.01 (s, 3H, CH₃), 3.91 (s, 3H, CH₃), 1.43 (t, J=7.6 Hz, 3H, CH₃).

LCMS (ESI+): m/z 292 (M+H)⁺, RT: 1.75 min.

1.7 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

A mixture of the compound obtained in step 1.6 (254 mg, 0.8720 mmol) andsodium hydroxide (42 mg, 1.046 mmol) in methanol (6 mL) and water (2 mL)was heated at 40° C. for 6 h. The reaction mixture was concentrated invacuo. The concentrate was acidified with HCl (conc.) to pH=2˜3. Theresulting precipitates were collected by filtration. The solid was driedin vacuo and used in the next step without further purification (200 mg,yield 83%).

LCMS (ESI+): m/z 278 (M+H)⁺, RT: 1.50 min.

1.8 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

A suspension of the compound obtained in step 1.7 (50 mg, 0.1803 mmol)and thionyl chloride (64 mg, 0.5409 mmol) in DCM (3 mL) was refluxed for3 h. The mixture was concentrated in vacuo and diluted in DCM (3 mL).The solution was added dropwise to a mixture of n-butylamine (26 mg,0.3606 mmol) and triethylamine (55 mg, 0.5409 mmol) in DCM (4 mL) atambient temperature. The reaction mixture was stirred at r.t. foranother 3 h. Then the solvent was removed under reduced pressure, theresidue was diluted with EtOAc and washed with HCl (2 N), NaOH (2 N) andbrine successively. The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified on silica gel column(eluted with DCM/EtOAc=4:1, v/v) to afford the title product as a whitesolid (53 mg, yield 88%).

LCMS: 1.70 min; M+H: 333.1

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.80 (s, 1H, ArH), 7.57 (s, 1H, ArH),7.35 (s, 1H, ArH), 5.96 (s, 1H, NH), 4.05 (q, J=7.6 Hz, 2H, CH₂), 4.01(s, 3H, OCH₃), 3.99 (s, 3H, OCH₃), 3.48 (q, J=5.6 Hz, 2H, CH₂),1.59-1.69 (m, 2H, CH₂), 1.41-1.51 (m, 2H, CH₂), 1.39 (t, J=6.8 Hz, 3H,CH₃), 0.99 (t, J=7.2 Hz, 3H, CH₃).

The following compounds were synthesized analogously, using in the lastreaction step the respective amine.

Example 22-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethylamide

LCMS: 1.54 min; M+H: 291

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.72 (s, 1H), 7.52 (s, 1H), 7.29 (s, 1H),5.97 (s, 1H), 3.96 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.97 (d, J=4.8Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).

Example 32-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethylamide

LCMS: 1.62 min; M+H: 305

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.80 (s, 1H), 7.59 (s, 1H), 7.35 (s, 1H),5.94 (s, 1H), 4.04 (m, 2H), 4.00 (s, 3H), 3.99 (s, 3H), 3.52 (m, 2H),1.39 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.4 Hz, 3H).

Example 42-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-fluoro-ethyl)-amide

LCMS: 1.56 min; M+H: 323

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H),6.26 (s, 1H), 4.66 (t, J=4.6 Hz, 1H), 4.54 (t, J=4.8 Hz, 1H), 3.99 (m,2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.77 (m, 1H), 3.70 (m, 1H), 1.33 (t,J=7.2 Hz).

Example 52-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2,2,2-trifluoro-ethyl)-amide

LCMS: 1.77 min; M+H: 359

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.81 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H),6.21 (s, 1H), 4.13-4.18 (m, 2H), 4.06 (m, 2H), 4.01 (s, 3H), 3.99 (s,3H), 1.41 (t, J=5.6 Hz, 3H).

Example 62-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopropylamide

LCMS: 1.50 min; M+H: 317

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.71 (s, 1H), 7.56 (s, 1H), 7.24 (s, 1H),6.06 (s, 1H), 3.96 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.85-2.88 (m,1H), 1.31 (t, J=7.4 Hz, 3H), 0.83-0.86 (m, 2H), 0.57-0.62 (m, 2H).

Example 72-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisopropylamide

LCMS: 1.58 min; M+H: 319

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.51 (s, 1H), 7.27 (s, 1H),5.65 (s, 1H), 4.20-4.29 (m, 1H), 3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.92(s, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.24 (d, J=6.4 Hz, 6H).

Example 82-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidpropylamide

LCMS: 1.59 min; M+H: 319

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.52 (s, 1H), 7.30 (s, 1H),5.85 (s, 1H), 3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.38 (br,2H), 1.59-1.65 (m, 2H), 1.33 (t, J=6.8 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H).

Example 92-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclobutylamide

LCMS: 1.74 min; M+H: 331

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.60 (s, 1H), 7.40 (s, 1H),6.02 (s, 1H), 4.63 (br, 1H), 4.10 (br, 2H), 4.01 (s, 3H), 4.00 (s, 3H),2.48 (br, 2H), 1.99 (m, 2H), 1.80 (br, 2H), 1.41 (br, 3H).

Example 102-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopropylmethyl-amide

LCMS: 1.72 min; M+H: 331

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.76 (s, 1H), 7.54 (s, 1H), 7.34 (s, 1H),5.94 (s, 1H), 3.99-4.04 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.26-3.29(m, 2H), 1.34 (t, J=7.2 Hz, 3H), 0.98-1.07 (m, 1H), 0.51-0.55 (m, 2H),0.23-0.27 (m, 2H).

Example 112-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidtert-butylamide

LCMS: 1.72 min; M+H: 333

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.45 (s, 1H), 7.26 (s, 1H),5.66 (s, 1H), 3.97-4.01 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.44 (s,9H), 1.33 (t, J=7.0 Hz, 3H).

Example 122-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidsec-butylamide

LCMS: 1.67 min; M+H: 333

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H),5.63 (s, 1H), 4.08 (m, 1H), 3.98-4.01 (m, 2H), 3.94 (s, 3H), 3.92 (s,3H), 1.49-1.55 (m, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H),0.95 (t, J=7.4 Hz, 3H).

Example 132-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisobutyl-amide

LCMS: 1.69 min; M+H: 333

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.50 (s, 1H), 7.29 (s, 1H),5.88 (s, 1H), 3.97-4.02 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.25 (t,J=6.4 Hz, 2H), 1.84-1.90 (m, 1H), 1.33 (t, J=7.2 Hz, 3H), 0.96 (d, J=6.4Hz, 6H).

Example 142-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopentylamide

LCMS: 1.71 min; M+H: 345

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.50 (s, 1H), 7.27 (s, 1H),5.77 (s, 1H), 4.34-4.39 (m, 1H), 3.97-4.02 (m, 2H), 3.94 (s, 3H), 3.92(s, 3H), 2.05-2.10 (m, 2H), 1.61-1.69 (m, 4H), 1.43-1.46 (m, 2H), 1.33(t, J=7.2 Hz, 3H).

Example 152-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-methyl-butyl)-amide

LCMS: 1.88 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H),5.67 (s, 1H), 4.21-4.27 (m, 1H), 4.05-4.09 (m, 2H), 4.01 (s, 3H), 3.99(s, 3H), 1.52-1.59 (m, 2H), 1.43-1.48 (m, 2H), 1.40 (t, J=5.4 Hz, 3H),1.28 (d, J=5.2 Hz, 3H), 0.98 (t, J=5.6 Hz, 3H).

Example 162-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1,1-dimethyl-propyl)-amide

LCMS: 1.91 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.86 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H),5.63 (s, 1H), 4.13 (m, 2H), 4.03 (s, 3H), 4.00 (s, 3H), 1.88-1.93 (m,2H), 1.46 (s, 6H), 1.41 (br, 3H), 0.97 (t, J=5.8 Hz, 3H).

Example 172-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1,2-dimethyl-propyl)-amide

LCMS: 1.86 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.76 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H),5.61 (s, 1H), 3.96-4.03 (m, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 1.77 (m,1H), 1.34 (t, J=7.2 Hz, 3H), 1.16 (d, J=6.8 Hz, 3H), 0.94 (d, J=4.0 Hz,3H), 0.93 (d, J=4.0 Hz, 3H).

Example 182-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2,2-dimethyl-propyl)-amide

LCMS: 1.89 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H),5.99 (s, 1H), 4.07 (br, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.31 (s, 2H),1.40 (s, 3H), 1.03 (s, 9H).

Example 192-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-ethyl-propyl)-amide

LCMS: 1.86 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.55 (s, 1H), 7.35 (s, 1H),5.55 (s, 1H), 4.03-4.09 (m, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 1.64-1.70(m, 2H), 1.51-1.55 (m, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.02 (t, J=7.4 Hz,6H).

Example 202-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-methyl-butyl)-amide

LCMS: 1.89 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.76 (s, 1H), 7.50 (s, 1H), 7.29 (s, 1H),5.83 (s, 1H), 3.98-4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.33-3.39(m, 1H), 3.21-3.27 (m, 1H), 1.61-1.68 (m, 1H), 1.41-1.47 (m, 1H), 1.33(t, J=5.6 Hz, 3H), 1.16-1.22 (m, 1H), 0.94 (d, J=5.6 Hz, 3H), 0.90 (t,J=6.0 Hz, 3H).

Example 212-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidpentylamide

LCMS: 1.91 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H),5.92 (s, 1H), 4.08-4.11 (m, 2H), 4.03 (s, 3H), 4.01 (s, 3H), 3.47-3.51(s, 2H), 1.68 (m, 2H), 1.42 (m, 7H), 0.96 (t, J=7.2 Hz, 3H).

Example 222-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclohexylamide

LCMS: 1.90 min; M+H: 359

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.51 (s, 1H), 7.29 (s, 1H),5.69 (s, 1H), 3.98-4.02 (m, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 2.01-2.03(m, 2H), 1.71-1.73 (m, 2H), 1.38-1.42 (m, 2H), 1.33 (t, J=4.8 Hz, 3H),1.16-1.22 (m, 4H).

Example 232-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1,3-dimethyl-butyl)-amide

LCMS: 1.97 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.74 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H),5.62 (s, 1H), 4.23-4.27 (m, 1H), 3.96-4.02 (m, 2H), 3.94 (s, 3H), 3.92(s, 3H), 1.65 (m, 1H), 1.41 (m, 1H), 1.33 (m, 4H), 1.21 (d, J=6.4 Hz,3H), 0.93 (d, J=6.4 Hz, 3H), 0.90 (d, J=6.8 Hz, 3H).

Example 242-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3,3-dimethyl-butyl)-amide

LCMS: 1.98 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.54 (s, 1H), 7.28 (s, 1H),5.71 (s, 1H), 3.98-4.02 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.42 (s,2H), 1.48 (m, 2H), 1.33 (t, J=5.4 Hz, 3H), 0.93 (s, 9H).

Example 252-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-ethyl-butyl)-amide

LCMS: 1.98 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.56 (s, 1H), 7.38 (s, 1H),5.87 (s, 1H), 4.06-4.10 (m, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.44-3.46(m, 2H), 1.52-1.55 (m, 1H), 1.40-1.45 (m, 7H), 0.96 (t, J=6.4 Hz, 3H).

Example 262-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbenzylamide

LCMS: 1.84 min; M+H: 367

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.56 (s, 1H), 7.33-7.42 (m,6H), 6.16 (s, 1H), 4.67 (s, 2H), 4.03-4.07 (m, 2H), 4.00 (s, 3H), 3.90(s, 3H), 1.39 (m, 3H).

Example 272-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddicyclopropylmethyl-amide

LCMS: 1.91 min; M+H: 371

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H),5.85 (s, 1H), 4.00-4.04 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.26 (m,1H), 1.34 (t, J=7.0 Hz, 3H), 0.93 (m, 2H), 0.54 (m, 2H), 0.37-0.45 (m,6H).

Example 282-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclohexylmethyl-amide

LCMS: 2.00 min; M+H: 373

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H),5.95 (s, 1H), 4.04-4.08 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.33 (s,2H), 1.76-1.84 (m, 4H), 1.68-1.72 (m, 2H), 1.40 (s, 3H), 1.21-1.29 (m,3H), 1.02-1.06 (m, 2H).

Example 292-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-phenyl-ethyl)-amide

LCMS: 1.89 min; M+H: 381

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.69 (s, 1H), 7.38-7.40 (m, 2H),7.31-7.35 (m, 4H), 7.22-7.25 (m, 1H), 6.25 (s, 1H), 5.33 (s, 1H),3.92-3.96 (m, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 1.59 (d, J=5.2 Hz, 3H),1.31 (s, 3H).

Example 302-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-fluoro-benzylamide

LCMS: 1.86 min; M+H: 385

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.81 (s, 1H), 7.53 (s, 1H), 7.46-7.49 (m,1H), 7.41 (s, 1H), 7.30.7.33 (m, 1H), 7.15-7.18 (m, 1H), 7.08-7.12 (m,1H), 6.28 (s, 1H), 4.72 (d, J=4.4 Hz, 2H), 4.03-4.08 (m, 2H), 4.00 (s,3H), 3.92 (s, 3H), 1.38 (d, J=5.8 Hz, 3H).

Example 312-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3-fluoro-benzylamide

LCMS: 1.87 min; M+H: 385

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H),7.33-7.37 (m, 1H), 7.18 (d, J=6.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H),7.00-7.04 (m, 1H), 6.22 (s, 1H), 4.67 (d, J=4.8 Hz, 2H), 4.04-4.08 (m,2H), 4.00 (s, 3H), 3.94 (s, 3H), 1.39 (d, J=5.2 Hz, 3H).

Example 322-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid4-fluoro-benzylamide

LCMS: 1.86 min; M+H: 385

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.78 (s, 1H), 7.55 (s, 1H), 7.38-7.41 (m,3H), 7.05-7.09 (m, 2H), 6.32 (s, 1H), 4.63 (d, J=4.4 Hz, 2H), 4.00-4.04(m, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 1.37 (d, J=5.6 Hz, 3H).

Example 332-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2,3-difluoro-benzylamide

LCMS: 1.90 min; M+H: 403

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.81 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H),7.24 (m, 1H), 7.08-7.16 (m, 2H), 6.29 (s, 1H), 4.73 (d, J=5.6 Hz, 2H),4.04-4.07 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 1.39 (t, J=7.2 Hz, 3H).

Example 342-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2,4-difluoro-benzylamide

LCMS: 1.90 min; M+H: 403

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.74 (s, 1H), 7.47 (s, 1H), 7.36-7.43 (m,1H), 7.32 (s, 1H), 6.76-6.85 (m, 2H), 6.17 (s, 1H), 4.59 (d, J=5.6 Hz,2H), 3.96-4.01 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 1.32 (t, J=7.2 Hz,3H).

Example 352-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2,6-difluoro-benzylamide

LCMS: 1.86 min; M+H: 403

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.47 (s, 1H), 7.25 (s, 1H),7.19 (m, 1H), 6.88 (m, 2H), 6.16 (s, 1H), 4.71 (d, J=5.2 Hz, 2H),3.96-4.01 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).

Example 362-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3,4-difluoro-benzylamide

LCMS: 1.91 min; M+H: 403

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.74 (s, 1H), 7.51 (s, 1H), 7.33 (s, 1H),7.06-7.17 (m, 3H), 6.17 (s, 1H), 4.55 (d, J=5.6 Hz, 2H), 3.96-4.02 (m,2H), 3.93 (s, 3H), 3.88 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).

Example 372-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3,5-difluoro-benzylamide

LCMS: 1.92 min; M+H: 403

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.74 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H),6.85-6.89 (m, 2H), 6.67-6.72 (m, 1H), 6.24 (s, 1H), 4.58 (d, J=6.0 Hz,2H), 3.97-4.02 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.33 (t, J=7.0 Hz,3H).

Example 382-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidphenethyl-amide

LCMS: 1.88 min; M+H: 381

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.79 (s, 1H), 7.55 (s, 1H), 7.33-7.36 (s,2H), 7.25-7.28 (m, 3H), 7.16 (s, 1H), 5.88 (s, 1H), 3.93-4.01 (m, 8H),3.76 (s, 2H), 3.00 (t, J=5.2 Hz, 3H), 1.36 (t, J=4.8 Hz, 3H).

Example 392-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid[1-(4-fluoro-phenyl)-ethyl]-amide

LCMS: 1.92 min; M+H: 399

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.41-7.44 (m, 3H), 7.35 (s,1H), 7.07 (m, 2H), 6.23 (s, 1H), 5.37 (s, 1H), 4.01-4.04 (m, 2H), 3.97(s, 3H), 3.88 (s, 3H), 1.64 (d, J=5.6 Hz, 2H), 1.38 (t, J=5.2 Hz, 3H).

Example 402-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidindan-1-ylamide

LCMS: 1.94 min; M+H: 393

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.58 (s, 1H), 7.34-7.38 (m,2H), 7.17-7.23 (m, 3H), 6.05 (m, 1H), 5.66 (s, 1H), 3.96-4.00 (m, 2H),3.93 (s, 3H), 3.90 (s, 3H), 2.97-3.03 (m, 1H), 2.86-2.71 (m, 1H),2.64-2.71 (m, 1H), 1.89-1.95 (m, 1H), 1.32 (t, J=5.2 Hz, 3H).

Example 412-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidindan-2-ylamide

LCMS: 1.93 min; M+H: 393

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.80 (s, 1H), 7.47 (s, 1H), 7.39 (s, 1H),7.28-7.30 (m, 2H), 7.20-7.22 (m, 2H), 6.15 (s, 1H), 4.96 (s, 1H),3.98-4.05 (m, 5H), 3.83 (s, 3H), 3.43-3.48 (m, 2H), 2.96-3.01 (m, 2H),1.37 (s, 3H).

Example 422-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide

LCMS: 1.98 min; M+H: 413

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.44-7.47 (m, 3H), 7.39 (s,1H), 7.03-7.07 (m, 2H), 6.18 (s, 1H), 4.06-4.10 (m, 2H), 4.00 (s, 3H),3.92 (s, 3H), 1.84 (s, 6H), 1.42 (s, 3H).

Example 434-(Azetidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.58 min; M+H: 317

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.76 (s, 1H), 7.42 (s, 1H), 7.20 (s, 1H),4.13 (t, J=7.6 Hz, 4H), 3.98-4.03 (m, 2H), 3.94 (s, 6H), 2.24-2.32 (m,2H), 1.32 (t, J=7.2 Hz, 3H).

Example 442-Ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one

LCMS: 1.74 min; M+H: 345

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.18 (s, 1H), 7.03 (br,1H), 4.41 (br, 1H), 4.03-4.07 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.38(br, 2H), 1.63-2.13 (m, 4H), 1.39 (t, J=5.6 Hz, 3H), 1.15-1.41 (br, 3H).

Example 452-Ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin-1-one

LCMS: 1.54 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.78 (s, 1H), 7.10 (s, 1H), 6.87 (s, 1H),3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.48-3.64 (br, 8H), 1.33(t, J=7.4 Hz, 3H).

Example 462-Ethyl-4-(3-fluoro-pyrrolidine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.61 min; M+H: 349

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.17 (s, 1H), 6.94 (s, 1H),5.22-5.34 (br, 1H), 3.98-4.03 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H),3.44-3.76 (br, 4H), 2.25 (br, 1H), 1.95-2.06 (br, 1H), 1.33 (t, J=7.0Hz, 3H).

Example 472-Ethyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinolin-1-one

LCMS: 1.52 min; M+H: 360

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H),3.97-4.01 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.61 (br, 4H), 2.41 (br,4H), 2.30 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).

Example 484-(3,3-Difluoro-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.74 min; M+H: 367

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.23 (s, 1H), 7.00 (s, 1H),4.06-4.10 (m, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.86 (br, 4H), 2.43 (s,2H), 1.40 (t, J=6.0 Hz, 3H).

Example 494-(3-Dimethylamino-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.55 min; M+H: 374

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.22 (s, 1H), 7.03 (s, 1H),4.04-4.09 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 2.81-3.57 (br, 4H),1.61-2.33 (m, 9H), 1.39 (t, J=5.6 Hz, 3H).

Example 502-Ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one

LCMS: 1.72 min; M+H: 375

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.25 (s, 1H), 7.13 (s, 1H),4.45 (br, 1H), 4.06-4.10 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.37-3.49(m, 5H), 1.76-2.08 (m, 4H), 1.41 (s, 3H).

Example 514-(1,3-Dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.86 min; M+H: 379

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.87 (s, 1H), 7.27-7.37 (m, 4H), 7.16 (s,1H), 7.01 (s, 1H), 5.07 (s, 2H), 4.75 (s, 2H), 4.07-4.11 (m, 2H), 4.02(s, 3H), 3.90 (s, 3H), 1.42 (t, J=5.2 Hz, 3H).

Example 524-(4,4-Difluoro-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.80 min; M+H: 381

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.19 (s, 1H), 6.90 (s, 1H),5.07 (s, 2H), 4.75 (s, 2H), 4.04-4.07 (m, 2H), 4.02 (s, 3H), 3.96 (s,3H), 3.73 (br, 4H), 2.02 (br, 4H), 1.40 (t, J=5.4 Hz, 3H).

Example 532-Ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.70 min; M+H: 388

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.16 (s, 1H), 6.93 (s, 1H),4.03-4.08 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.29-3.79 (br, 4H), 2.73(s, 1H), 2.51 (br, 4H), 1.40 (t, J=5.6 Hz, 3H), 1.05 (d, J=4.8 Hz, 6H).

Example 544-(4-Dimethylamino-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.50 min; M+H: 388

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.14 (s, 1H), 6.92 (s, 1H),4.08 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 2.96 (s, 2H), 2.35-2.43 (br,7H), 1.97 (br, 2H), 1.53 (br, 4H), 1.39 (t, J=7.0 Hz, 3H).

Example 552-Ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one

LCMS: 1.89 min; M+H: 399

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.32 (s, 1H), 7.09 (s, 1H),5.16 (s, 1H), 4.02-4.12 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.47 (t,J=5.6 Hz, 2H), 2.15-2.25 (m, 2H), 2.04-2.09 (m, 1H), 1.88-1.93 (m, 1H),1.41 (t, J=5.8 Hz, 3H).

Example 564-(4-Cyclopropylmethyl-piperazine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.74 min; M+H: 400

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.16 (s, 1H), 6.93 (s, 1H),4.02-4.08 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.63 (br, 4H), 2.55 (br,4H), 2.31 (s, 2H), 1.40 (t, J=6.4 Hz, 3H), 0.87 (s, 1H), 0.54 (s, 2H),0.12 (s, 2H).

Example 572-Ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one

LCMS: 1.65 min; M+H: 414

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.26 (s, 1H), 7.05 (s, 1H),4.59 (br, 1H), 4.04-4.42 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.45 (br,2H), 2.76 (br, 6H), 1.38-2.05 (m, 8H), 1.40 (t, J=5.8 Hz, 3H).

Example 582-Ethyl-6,7-dimethoxy-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-2H-isoquinolin-1-one

LCMS: 1.58 min; M+H: 414

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.13 (s, 1H), 6.92 (s, 1H),4.66 (br, 1H), 4.05 (s, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.02 (br, 4H),2.64 (br, 4H), 2.36 (br, 2H), 2.00 (br, 2H), 1.85 (br, 4H), 1.38 (t,J=6.0 Hz, 3H).

Example 594-[4-(2-Dimethylamino-ethyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.46 min; M+H: 417

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.15 (s, 1H), 6.92 (s, 1H),4.07 (s, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.67 (br, 4H), 2.53-2.68 (m,14H), 1.39 (t, J=5.6 Hz, 3H).

Example 604-([1,4′]Bipiperidinyl-1′-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.66 min; M+H: 428

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.14 (br, 1H), 6.89 (br,1H), 3.79-4.83 (b, 10H), 2.93 (br, 4H), 2.55 (br, 4H), 1.97 (br, 4H),1.63 (br, 5H), 1.39 (t, J=5.6 Hz, 3H).

Example 614-[4-(3-Dimethylamino-propyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one

LCMS: 1.45 min; M+H: 431

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.14 (s, 1H), 6.92 (s, 1H),4.06 (br, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.63 (br, 4H), 2.80 (br, 2H),2.59 (br, 6H), 2.46 (br, 6H), 1.92 (br, 2H), 1.39 (t, J=6.0 Hz, 3H).

Example 622-Ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-2H-isoquinolin-1-one

LCMS: 1.48 min; M+H: 443

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.08 (s, 1H), 6.85 (s, 1H),3.99 (m, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.56 (br, 4H), 2.45-2.67 (br,11H), 1.81 (br, 5H), 1.32 (t, J=7.2 Hz, 3H).

Example 632-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddimethylamide

LCMS: 1.55 min; M+H: 305

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.15 (s, 1H), 6.90 (s, 1H),4.07 (br, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.10 (br, 6H), 1.39 (t, J=4.8Hz, 3H).

Example 642-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-methyl-amide

LCMS: 1.63 min; M+H: 319

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.12 (s, 1H), 6.87 (s, 1H),4.04-4.09 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.50 (br, 2H), 3.04 (br,3H), 1.39 (t, J=7.2 Hz, 3H), 1.21 (br, 3H).

Example 652-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisopropyl-methyl-amide

LCMS: 1.73 min; M+H: 333

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.78 (s, 1H), 7.02 (s, 1H), 6.76 (s, 1H),3.99 (m, 3H), 3.94 (s, 3H), 3.87 (s, 3H), 2.85 (br, 3H), 1.32 (t, J=7.2Hz, 3H), 1.14 (s, 6H).

Example 662-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddiethylamide

LCMS: 1.72 min; M+H: 333

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.10 (s, 1H), 6.85 (s, 1H),4.08 (br, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.56 (br, 4H), 3.04 (br, 3H),1.40 (br, 3H), 1.21 (br, 6H).

Example 672-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl-propyl-amide

LCMS: 1.73 min; M+H: 333

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.11 (s, 1H), 6.88 (s, 1H),4.07 (br, 2H), 4.02 (s, 3H), 3.95 (s, 3H), 3.42 (br, 2H), 3.02 (br, 3H),1.63 (br, 2H), 1.39 (br, 3H), 0.89 (br, 3H).

Example 682-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-isopropyl-amide

LCMS: 1.81 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.06 (s, 1H), 6.85 (s, 1H),4.07 (br, 3H), 4.01 (s, 3H), 3.93 (s, 3H), 3.34-3.60 (br, 2H), 1.39 (t,J=5.6 Hz, 3H), 1.19 (br, 9H).

Example 692-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidtert-butyl-methyl-amide

LCMS: 1.87 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.13 (s, 1H), 6.98 (s, 1H),4.00 (m, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 2.80 (s, 3H), 1.51 (s, 9H),1.33 (t, J=6.8 Hz, 3H).

Example 702-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisobutyl-methyl-amide

LCMS: 1.83 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.78 (s, 1H), 7.03 (s, 1H), 6.82 (s, 1H),4.00 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.36 (br, 2H), 2.95 (br, 3H),1.95 (br, 1H), 1.32 (t, J=6.8 Hz, 3H), 0.78-0.91 (br, 6H).

Example 712-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutyl-methyl-amide

LCMS: 1.84 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.11 (s, 1H), 6.87 (s, 1H),4.04-4.09 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.44 (br, 2H), 3.03 (br,3H), 1.65 (br, 2H), 1.39 (t, J=5.8 Hz, 3H), 1.19 (br, 2H), 0.82 (br,3H).

Example 722-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-propyl-amide

LCMS: 1.82 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H),4.01 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.26-3.43 (br, 4H), 1.61 (br,2H), 1.32 (t, J=7.2 Hz, 3H), 1.10 (br, 3H), 0.81 (br, 3H).

Example 732-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-dimethylamino-ethyl)-methyl-amide

LCMS: 1.56 min; M+H: 362

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.20 (s, 1H), 7.00 (s, 1H),4.04-4.10 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.47-3.71 (br, 2H), 3.01(s, 3H), 2.58 (br, 2H), 2.28 (br, 6H), 1.40 (t, J=7.2 Hz, 3H).

Example 742-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-(2-methoxy-ethyl)-amide

LCMS: 1.70 min; M+H: 363

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.10 (s, 1H), 6.87 (s, 1H),3.96-4.02 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.29-3.52 (br, 9H), 1.32(t, J=7.2 Hz, 3H), 1.07 (br, 3H).

Example 752-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopentyl-methyl-amide

LCMS: 1.86 min; M+H: 359

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H),4.07 (br, 3H), 4.02 (s, 3H), 3.94 (s, 3H), 2.95 (br, 3H), 1.59-1.72 (m,6H), 1.56 (br, 2H), 1.40 (br, 3H).

Example 762-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-butyl-amide

LCMS: 1.93 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.78 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H),3.97-4.02 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.20-3.48 (br, 4H), 1.44(br, 4H), 1.32 (t, J=5.4 Hz, 3H), 0.78-1.11 (br, 6H).

Example 772-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl-pentyl-amide

LCMS: 1.94 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.12 (s, 1H), 6.87 (s, 1H),4.07 (br, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 2.97-3.59 (br, 5H), 1.60 (br,4H), 1.39 (br, 3H), 1.23 (br, 2H), 0.87 (br, 3H).

Example 782-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddiisopropylamide

LCMS: 1.92 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 6.99 (s, 1H), 6.86 (s, 1H),4.02-4.08 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.74 (br, 2H), 1.38 (t,J=7.2 Hz, 3H), 1.36 (br, 12H).

Example 792-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisopropyl-propyl-amide

LCMS: 1.91 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.05 (s, 1H), 6.85 (s, 1H),4.06 (br, 3H), 4.01 (s, 3H), 3.93 (s, 3H), 3.18-3.44 (br, 2H), 1.69 (br,2H), 1.38 (t, J=5.8 Hz, 3H), 0.98-1.17 (br, 9H).

Example 802-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddipropylamide

LCMS: 1.92 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.65 (s, 1H), 7.51 (s, 1H), 6.75 (s, 1H),3.97-4.03 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.42 (s, 2H), 3.13 (s,2H), 1.47-1.67 (br, 4H), 1.23 (t, J=7.0 Hz, 3H), 0.66-0.95 (br, 6H).

Example 812-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-dimethylamino-propyl)-methyl-amide

LCMS: 1.48 min; M+H: 376

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.09 (s, 1H), 6.81 (s, 1H),3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.44 (br, 3H), 3.00 (s,3H), 1.84-2.17 (br, 9H), 1.32 (t, J=7.2 Hz, 3H).

Example 822-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclohexyl-methyl-amide

LCMS: 1.93 min; M+H: 373

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.78 (s, 1H), 7.02 (s, 1H), 6.78 (s, 1H),3.97-4.03 (m, 3H), 3.94 (s, 3H), 3.87 (s, 3H), 2.73-2.95 (br, 3H),1.51-1.74 (br, 8H), 1.32 (t, J=5.8 Hz, 3H), 1.01 (br, 2H).

Example 832-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopropylmethyl-propyl-amide

LCMS: 1.94 min; M+H: 373

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.77 (s, 1H), 7.03 (s, 1H), 6.83 (s, 1H),3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.28 (br, 4H), 1.52 (br,1H), 1.32 (t, J=7.2 Hz, 3H), 0.81 (br, 4H), 0.48 (s, 2H).

Example 842-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddiisobutylamide

LCMS: 2.08 min; M+H: 389

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.85 (s, 1H), 7.06 (s, 1H), 6.93 (s, 1H),4.04-4.09 (m, 2H), 4.02 (s, 3H), 3.93 (s, 3H), 3.07-3.42 (br, 4H),1.88-2.15 (br, 2H), 1.39 (t, J=5.6 Hz, 3H), 1.05 (br, 6H), 0.77 (br,6H).

Example 852-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbenzyl-methyl-amide

LCMS: 1.88 min; M+H: 381

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.24-7.32 (m, 4H), 7.08 (s,2H), 6.70 (br, 1H), 4.65 (br, 2H), 3.65-3.93 (br, 8H), 2.86 (br, 3H),1.26 (s, 3H).

Example 862-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-fluoro-benzyl)-methyl-amide

LCMS: 1.89 min; M+H: 399

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.40 (br, 1H), 7.29-7.34(m, 1H), 7.15-7.18 (m, 2H), 7.06-7.10 (m, 1H), 6.79 (br, 1H), 4.79 (br,2H), 4.02-4.06 (m, 2H), 4.00 (s, 3H), 3.79 (br, 3H), 2.97 (br, 3H), 1.36(br, 3H).

Example 872-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-fluoro-benzyl)-methyl-amide

LCMS: 1.90 min; M+H: 399

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.40 (br, 1H), 7.15 (br,2H), 7.06 (m, 2H), 6.73 (br, 1H), 4.70 (br, 2H), 4.04 (br, 2H), 4.00 (s,3H), 3.79 (br, 3H), 2.93 (br, 3H), 1.35 (br, 3H).

Example 882-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-fluoro-benzyl)-methyl-amide

LCMS: 1.90 min; M+H: 399

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.32-7.36 (m, 1H),6.82-7.16 (m, 5H), 4.74 (br, 2H), 4.04 (br, 2H), 4.00 (s, 3H), 3.80 (br,3H), 2.93 (br, 3H), 1.36 (br, 3H).

Example 892-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl-phenethyl-amide

LCMS: 1.89 min; M+H: 395

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.19 (br, 5H), 7.02 (br,1H), 6.72 (br, 1H), 3.93 (s, 3H), 3.87 (br, 2H), 3.82 (s, 3H), 3.44 (br,2H), 2.86-3.08 (br, 5H), 1.26 (t, J=7.0 Hz, 3H).

Example 902-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-methoxy-benzyl)-methyl-amide

LCMS: 1.89 min; M+H: 411

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.24 (s, 1H), 6.80-7.06 (m,5H), 4.45-4.75 (br, 2H), 3.65-3.93 (m, 11H), 2.83-3.06 (m, 3H), 1.18(br, 3H).

Example 912-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-methoxy-benzyl)-methyl-amide

LCMS: 1.86 min; M+H: 411

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.38 (br, 1H), 6.72-7.15(m, 5H), 3.72-4.69 (m, 13H), 2.88 (br, 3H), 1.35 (br, 3H).

Example 922-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-methoxy-benzyl)-methyl-amide

LCMS: 1.88 min; M+H: 411

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.76 (s, 1H), 7.22 (m, 2H), 6.76-7.09 (m,4H), 4.60 (br, 2H), 3.73-3.93 (m, 11H), 2.85 (br, 3H), 1.27 (br, 3H).

Example 932-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl-(3-trifluoromethyl-benzyl)-amide

LCMS: 202 min; M+H: 449

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.76 (s, 1H), 7.52 (m, 3H), 7.45 (m, 1H),7.09 (s, 1H), 6.75 (s, 1H), 4.71 (s, 2H), 3.96 (s, 2H), 3.93 (s, 3H),3.74 (s, 3H), 2.91 (s, 3H), 1.27 (s, 3H).

Example 942-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbenzyl-(2-dimethylamino-ethyl)-amide

LCMS: 1.88 min; M+H: 438

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.75 (s, 1H), 7.23-7.27 (m, 4H), 7.08(br, 3H), 4.47 (br, 2H), 3.17-3.93 (m, 10H), 1.98-2.53 (m, 8H), 1.22 (s,3H).

Example 952-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-benzyl-piperidin-4-yl)-methyl-amide

LCMS: 1.94 min; M+H: 464

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.29 (br, 4H), 7.25 (br,1H), 7.10 (s, 1H), 6.81 (s, 1H), 4.02-4.08 (m, 3H), 4.01 (s, 3H), 3.91(s, 3H), 3.50 (br, 2H), 2.96 (br, 5H), 1.72-2.17 (m, 6H), 1.38 (t, J=5.8Hz, 3H).

The compounds of the following examples 96 to 118 were prepared inanalogy to example 1, where however, in step 1.6, ethylamine wasreplaced by the respective amine and in step 1.8 butylamine was usedinstead of methylamine.

Example 966,7-Dimethoxy-1-oxo-2-(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.94 min; M+H: 387

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H),5.85 (s, 1H), 4.68 (q, J=7.6 Hz, 2H), 4.01 (s, 3H), 4.00 (s, 3H), 3.48(q, J=5.6 Hz, 2H), 1.64 (m, 2H), 1.45 (m, 2H), 0.99 (t, J=7.2 Hz, 3H).

Example 972-(2-Fluoro-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.77 min; M+H: 351

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.80 (s, 1H), 7.66 (s, 1H), 7.39 (s, 1H),5.84 (s, 1H), 4.84 (s, 1H), 4.71 (s, 1H), 4.37 (s, 1H), 4.28 (s, 1H),4.01 (s, 6H), 3.46 (d, J=5.2 Hz, 2H), 1.61-1.65 (m, 2H), 1.41-1.48 (m,2H), 0.99 (t, J=7.6 Hz, 3H).

Example 982-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.81 min; M+H: 345

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.79 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H),6.10 (br, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.47-3.53 (m, 2H), 3.32-3.36(m, 1H), 1.64-1.71 (m, 2H), 1.45-1.53 (m, 2H), 1.14-1.20 (m, 2H), 0.99(t, J=7.2 Hz, 3H), 0.89-0.94 (m, 2H).

Example 992-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.85 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.56 (s, 1H), 7.40 (s, 1H),5.83 (br, 1H), 5.31-5.40 (m, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.46-3.53(m, 2H), 1.60-1.69 (m, 2H), 1.41-1.49 (m, 2H), 1.41 (d, J=6.8 Hz, 6H),0.99 (t, J=7.2 Hz, 3H).

Example 1006,7-Dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide

LCMS: 1.86 min; M+H: 347

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.61 (s, 1H), 7.36 (s, 1H),5.83 (br, 1H), 3.98-4.03 (m, 8H), 3.45-3.52 (m, 2H), 1.82 (br, 2H),1.60-1.68 (m, 2H), 1.41-1.50 (m, 2H), 0.99 (t, J=7.2 Hz, 3H).

Example 1016,7-Dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.94 min; M+H: 401

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.79 (s, 1H), 7.61 (s, 1H), 7.32 (s, 1H),5.81 (br, 1H), 4.22 (t, J=6.6 Hz, 2H), 4.01 (s, 6H), 3.45-3.51 (m, 2H),2.60-73 (m, 2H), 1.60-1.68 (m, 2H), 1.41-1.49 (m, 2H), 0.99 (t, J=7.4Hz, 3H).

Example 1026,7-Dimethoxy-2-(2-methoxy-ethyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.76 min; M+H: 363

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.81 (s, 1H), 7.69 (s, 1H), 7.45 (s, 1H),5.88 (br, 1H), 4.20 (t, J=4.8 Hz, 2H), 4.00 (s, 6H), 3.72 (t, J=4.8 Hz,2H), 3.43-3.51 (m, 2H), 3.33 (s, 3H), 1.58-1.67 (m, 2H), 1.41-1.49 (m,2H), 0.99 (t, J=7.4 Hz, 3H).

Example 1032-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.90 min; M+H: 359

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.81 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H),5.85 (br, 1H), 5.16-5.23 (m, 1H), 4.00 (s, 6H), 3.46-3.53 (m, 2H), 2.53(br, 2H), 2.25-2.29 (m, 2H), 1.88-1.92 (m, 2H), 1.60-1.69 (m, 2H),1.43-1.51 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).

Example 1042-tert-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.97 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.76 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H),5.75 (br, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.38-3.42 (m, 2H), 1.53-1.59(m, 2H), 1.35-1.41 (m, 2H), 1.18 (s, 9H), 0.92 (t, J=7.4 Hz, 3H).

Example 1052-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.93 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.57 (s, 1H), 7.33 (s, 1H),5.85 (br, 1H), 5.14-5.20 (m, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.46-3.51(m, 2H), 1.73-1.78 (m, 2H), 1.61-1.67 (m, 2H), 1.43-1.49 (m, 2H), 1.39(d, J=7.2, 3H), 0.99 (t, J=7.4 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H).

Example 1062-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.94 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.61 (s, 1H), 7.30 (s, 1H),5.85 (br, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.82 (d, J=7.6 Hz, 2H),3.45-3.50 (m, 2H), 2.17-2.23 (m, 1H), 1.61-1.67 (m, 2H), 1.42-1.49 (m,2H), 0.96-1.01 (m, 9H).

Example 1072-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide

LCMS: 1.98 min; M+H: 361

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.82 (s, 1H), 7.60 (s, 1H), 7.34 (s, 1H),5.83 (br, 1H), 3.99-4.03 (m, 8H), 3.45-3.50 (m, 2H), 1.73-1.78 (m, 2H),1.61-1.67 (m, 2H), 1.39-1.49 (m, 4H), 0.95-1.01 (m, 6H).

Example 1082-Cyclopropylmethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.88 min; M+H: 359

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H),5.83 (br, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.90 (d, J=6.8 Hz, 2H),3.45-3.51 (m, 2H), 1.60-1.66 (m, 2H), 1.42-1.50 (m, 2H), 1.23-1.29 (m,1H), 0.99 (t, J=7.4 Hz, 3H), 0.60-0.64 (m, 2H), 0.41-0.46 (m, 2H).

Example 1092-Cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.97 min; M+H: 373

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.83 (s, 1H), 7.55 (s, 1H), 7.40 (s, 1H),5.79 (br, 1H), 5.34-5.38 (m, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.46-3.52(m, 2H), 2.18-2.22 (m, 2H), 1.89 (br, 2H), 1.73-1.78 (m, 4H), 1.61-1.67(m, 2H), 1.42-1.50 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).

Example 1102-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 1.99 min; M+H: 375

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.86 (s, 1H), 7.59 (s, 1H), 7.26 (s, 1H),5.78 (br, 1H), 5.03 (br, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.45-3.51 (m,2H), 1.81-1.87 (m, 2H), 1.61-1.67 (m, 4H), 1.43-1.49 (m, 2H), 0.99 (t,J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 6H).

Example 1116,7-Dimethoxy-2-(2-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 2.00 min; M+H: 425

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.84 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H),7.33-7.36 (m, 1H), 7.25 (br, 1H), 6.89-6.95 (m, 2H), 5.77 (br, 1H), 5.22(s, 2H), 3.99 (s, 6H), 3.88 (s, 3H), 3.43-3.47 (m, 2H), 1.58-1.62 (m,2H), 1.41-1.47 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).

Example 1122-Indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

LCMS: 2.05 min; M+H: 421

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.89 (s, 1H), 7.61 (s, 1H), 7.30-7.38 (m,2H), 7.11 (s, 1H), 7.00 (s, 1H), 6.68 (br, 1H), 5.53 (br, 1H), 4.03 (s,4H), 3.99 (s, 3H), 3.36 (br, 2H), 3.05-3.14 (m, 2H), 2.82 (br, 1H), 2.05(br, 1H), 1.41-1.51 (m, 2H), 1.25-1.33 (m, 2H), 0.91 (t, J=6.8 Hz, 3H).

Example 1132-(2-Dimethylamino-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide Example 1146,7-Dimethoxy-1-oxo-2-(2-pyrrolidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide Example 1152-Benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide Example 1162-(2,4-Difluoro-benzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide Example 1176,7-Dimethoxy-1-oxo-2-(2-piperidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide Example 1186,7-Dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide Example 1193-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acidbutylamide 119.1 1-(4,5-Dimethoxy-2-methyl-phenyl)-ethanone

A solution of 1,2-dimethoxy-4-methylbenzene in CS₂ (20 mL) was addeddropwise to a mixture of acetyl chloride (2.063 g, 26.3 mmol) andaluminium trichloride (3.50 g, 26.3 mmol) in CS₂ (80 mL). The reactionmixture was stirred for 12 h at 25° C., then poured into ice-water andextracted with DCM. The organic layer was separated and concentrated.The obtained residue was purified by column chromatography on silica gel(PE: EtOAc=20:1) to give the title compound (3.2 g, 62%) as a yellowoil.

LCMS (ESI+): m/z 195 (M+H)⁺, RT: 0.776 min.

119.2 4,5-Dimethoxy-2-oxalyl-benzoic acid

A solution of potassium permanganate (11.39 g, 72.1 mmol) in water (45mL) was added dropwise to a mixture of1-(4,5-dimethoxy-2-methyl-phenyl)-ethanone obtained in step 119.1 (2 g,10.30 mmol) and potassium carbonate (2.135 g, 15.45 mmol) in H₂O (5 mL),and the reaction mixture was stirred for 3 h at 50° C. Then ethanol wasadded and the resulting mixture was stirred for 30 min. The solid wasfiltered off, the filtrate was adjusted to pH=2 with conc. HCl, EtOAcwas added, and the organic layer was separated and concentrated to givethe title compound (1.7 g, 64.9%) as a white solid.

LCMS (ESI+): m/z 255 (M+H)⁺, RT: 0.524 min.

119.3 6,7-Dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid

A solution of 4,5-dimethoxy-2-oxalyl-benzoic acid obtained in step 119.2(1.15 g, 4.52 mmol) and hydrazine hydrate (254 mg, 4.98 mmol) in ethanol(20 mL) was stirred for 2 h at 75° C. The solid was filtered to give thetitle compound (910 mg, 80%) as a white solid.

LCMS (ESI+): m/z 251 (M+H)⁺, RT: 0.587 min.

119.4 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid ethyl ester

A mixture of 6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid obtained in step 119.3 (500 mg, 1.998 mmol), cesium carbonate (1954mg, 6.00 mmol) and iodoethane (768 mg, 4.92 mmol) in DMF (8 mL) wasstirred at 65° C. for 12 h. Water was added, and the solid was filteredto give the title compound (300 mg, 49.0%) as a white solid.

LCMS (ESI+): m/z 307 (M+H)⁺, RT: 0.839 min.

119.5 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid

A solution of3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acidethyl ester obtained in step 119.4 (400 mg, 1.306 mmol) and lithiumhydroxide (46.9 mg, 1.959 mmol) in ethanol and water (2 mL) was stirredat 35° C. for 3 h. The reaction solution was adjusted to pH=4 withdilute HCl, and the solid was filtered and washed with water to give thetitle compound (280 mg, 77%) as a white solid.

LCMS (ESI+): m/z 279 (M+H)⁺, RT: 0.862 min.

119.6 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid butylamide

A solution of3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acidobtained in step 119.5 (200 mg, 0.719 mmol) in SOCl₂ (2 mL) was stirredat 76° C. for 2 h. Then SOCl₂ was removed and the residue was dissolvedin DCM (5 mL).

Butan-1-amine (79 mg, 1.078 mmol) and triethylamine (109 mg, 1.078 mmol)were added dropwise and the resulting reaction was stirred at r.t. for 3h. The solvent was removed and the obtained residue was washed withEtOAc to give the title compound (140 mg, 58.4%) as a white solid.

LCMS (ESI+): m/z 334 (M+H)⁺, RT: 1.910 min.

¹H-NMR (400 MHz, CDCl₃): δ 8.75 (s, 1H), 7.78 (s, 1H), 7.37 (br, 1H),4.33 (t, J=7.2 Hz, 2H), 4.06 (s, 6H), 3.47 (t, J=7.2 Hz, 2H), 1.65 (t,J=7.2 Hz, 2H), 1.47-1.42 (m, 5H), 0.98 (t, J=7.2 Hz, 3H).

The compounds of the following examples 120 to 132 were prepared inanalogy to example 119.

Example 1203-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amide

ESI-MS: [M+Na⁺]=444.20, [M+H⁺]=422.20;

Example 1213-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(R)-indan-1-ylamide

ESI-MS: [M+Na⁺]=416.10, [M+H⁺]=394.10;

Example 1223-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide

ESI-MS: [M+Na⁺]=430.10, [M+H⁺]=408.10;

Example 1233-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide

ESI-MS: [M+Na⁺]=430.10, [M+H⁺]=408.10;

Example 1243-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide

ESI-MS: [M+Na⁺]=444.10, [M+H⁺]=422.10;

Example 1253-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(1,2,3,4-tetrahydro-naphthalen-2-yl)-amide

ESI-MS: [M+Na⁺]=430.10, [M+H⁺]=408.10;

Example 1263-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(4-bromo-indan-1-yl)-amide

ESI-MS: 495.10, [M+Na⁺]=494.10, 474.10, [M⁺]=472.10;

Example 1273-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(5-bromo-indan-1-yl)-amide

ESI-MS: 496.00, [M+Na⁺]=494.00, 474.00, [M⁺]=472.00;

Example 1283-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid2-dimethylaminomethyl-benzylamide

ESI-MS: [M+H⁺]=425.20;

Example 1293-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

ESI-MS: [M+Na⁺]=417.10, [M+H⁺]=395.10;

Example 1303-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7-dihydro-5H-[1]pyrindin-7-yl)-amide

ESI-MS: [M+H⁺]=395.10;

Example 1313-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid3-dimethylaminomethyl-benzylamide

ESI-MS: [M+Na⁺]=447.20, [M+H⁺]=425.20;

Example 1323-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid4-dimethylaminomethyl-benzylamide

ESI-MS: [M+Na⁺]=447.20, [M+H⁺]=425.20;

Example 1332-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide 133.1 2-(2-Carboxy-4-methoxy-phenyl)-malonic acid dimethylester

To a solution of dimethyl malonate (45 mL) was added sodium (0.915 g,39.8 mmol), and the resulting mixture was stirred until sodium haddisappeared. Then copper(I) bromide (0.248 g, 1.731 mmol) and2-bromo-5-methoxy-benzoic acid (4 g, 17.31 mmol) were added and theresulting reaction was stirred at 70° C. for 12 h. Water and EtOAc wereadded and the organic layer was separated off. The aqueous layer wasacidified with conc. HCl, then EtOAc was added and the organic layer wasseparated and concentrated to give the title compound (3.2 g, 65.5%) asa yellow solid.

LCMS (ESI+): m/z 283 (M+H)⁺, RT: 0.724 min.

133.2 2-(2-Carboxy-4-methoxy-phenyl)-malonic acid

A solution of 2-(2-carboxy-4-methoxy-phenyl)-malonic acid dimethyl esterobtained in step 133.1 (2.5 g, 8.86 mmol) and lithium hydroxide (1.061g, 44.3 mmol) in CH₃OH (30 mL) and water (8 mL) was stirred for 12 h at40° C. The solvent was removed, the residue was adjusted pH=4 withdilute HCl, EtOAc was added, and the organic layer was separated andconcentrated to give the title compound (1.67 g, 74.2%) as a whitesolid.

LCMS (ESI+): m/z 255 (M+H)⁺, RT: 0.453 min.

133.3 2-Carboxymethyl-5-methoxy-benzoic acid

A suspension of 2-(2-carboxy-4-methoxy-phenyl)-malonic acid obtained instep 133.2 (200 mg, 0.787 mmol) in toluene (8 mL) was stirred for 12 hat 105° C. The solid was filtered to give the title compound (100 mg,60.5%) as a white solid.

LCMS (ESI+): m/z 211 (M+H)⁺, RT: 0.630 min.

133.4 5-Methoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester

A mixture of 2-carboxymethyl-5-methoxy-benzoic acid obtained in step133.3 (100 mg, 0.476 mmol) and sulfurous dichloride (170 mg, 1.427 mmol)in CH₃OH (10 mL) was stirred at 65° C. for 12 h. The solvent was removedto give the crude title compound (100 mg, 88%) as a yellow oil.

LCMS (ESI+): m/z 239 (M+H)⁺, RT: 0.820 min.

133.5 2-(2-Dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-benzoic acidmethyl ester

A solution of 5-methoxy-2-methoxycarbonylmethyl-benzoic acid methylester obtained in step 133.4 (700 mg, 2.94 mmol) and HOAc (0.5 mL) inDMF-DMA (15 mL) was stirred 12 h at 90° C., then poured to water andextracted with EtOAc. The organic layer was separated and concentratedto give a residue which was purified by Prep-TLC (PE: EtOAc=1:1) to givethe title compound (600 mg, 69.6%) as a yellow oil.

LCMS (ESI+): m/z 267 (M−27)⁺, RT: 0.735 min.

133.6 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl ester

A solution of2-(2-dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-benzoic acidmethyl ester obtained in step 133.5 (500 mg, 1.705 mmol), ethanamine(231 mg, 5.11 mmol) and DIPEA (1.5 ml) in MeOH (15 mL) was stirred at65° C. for 12 h. The solvent was removed, water and EtOAc were added tothe residue, the organic layer was separated and concentrated to givethe crude title compound (420 mg, 94%) as a white solid.

LCMS (ESI+): m/z 262 (M+H)⁺, RT: 0.867 min.

133.7 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid

2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl ester obtained in step 133.6 and lithium hydroxide (77 mg, 3.22mmol) in CH₃OH (15 mL) and water (2 mL) were stirred at 35° C. for 5 h.The reaction solution was concentrated and the obtained residue wasdissolved in water and adjusted pH=4 with dilute HCl. The solid wasfiltered to give the title compound (362 mg, 91%) as white solid.

LCMS (ESI+): m/z 248 (M+H)⁺, RT: 0.737 min.

133.8 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide

A solution of2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidobtained in step 133.7 (300 mg, 1.209 mmol) in SOCl₂ (4 mL) was stirredat 76° C. for 2 h; then SOCl₂ was removed. The obtained residue wasdissolved in DCM (6 mL) and butan-1-amine (133 mg, 1.813 mmol) andtriethylamine (183 mg, 1.813 mmol) were added dropwise. The resultingreaction was stirred at RT for 3 h. The solvent was removed and theobtained residue was washed with EtOAc to give the title compound (200mg, 0.659 mmol, 54.6% yield).

¹H-NMR (400 MHz, MeOD): 7.93 (d, J=8.8 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H),7.44 (s, 1H), 7.25 (dd, 9.2 Hz, 2.8 Hz, 1H), 4.01 (t, J=7.2 Hz, 2H),3.81 (s, 3H), 3.28 (t, J=7.6 Hz, 2H), 1.56-1.51 (m, 2H), 1.39-1.32 (m,2H), 1.28 (t, J=7.6 Hz, 3H), 0.89 (t, J=7.6 Hz, 3H).

The compounds of the following examples 134 to 136 were prepared inanalogy to example 133.

Example 1342-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide

ESI-MS: [M+Na⁺]=427.10, [M⁺]=405.10;

Example 1352-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide 135.12-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester

A solution of2-(2-dimethylamino-1-methoxycarbonylvinyl)-4,5-dimethoxy-benzoic acidmethyl ester obtained in step 1.5 (800 mg, 2.474 mmol), pentan-3-amine(323 mg, 3.71 mmol) and HOAc (1.5 mL) in MeOH (15 mL) was stirred at 65°C. for 12 h. The solvent was removed and water and EtOAc were added tothe obtained residue. The organic layer was separated and concentratedto give the title compound (750 mg, 91%) as a white solid.

LCMS (ESI+): m/z 334 (M+H)⁺, RT: 0.941 min.

135.22-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid

A mixture of2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester obtained in step 135.1 (750 mg, 2.250 mmol) andlithium hydroxide (108 mg, 4.50 mmol) in CH₃OH (8 mL) and water (2 mL)was stirred at 35° C. for 5 h. The reaction solution was concentratedand the obtained residue was dissolved in water and adjusted pH=4 withdilute HCl. The solid was filtered to give the title compound (700 mg,97%) as a white solid.

LCMS (ESI+): m/z 320 (M+H)⁺, RT: 0.804 min.

135.32-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide

A solution of2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid obtained in step 135.2 (300 mg, 0.939 mmol) in SOCl₂ (5 mL) wasstirred at 76° C. for 2 h. SOCl₂ was removed. The obtained residue wasdissolved in DCM (5 mL), 2,3-dihydro-1H-inden-1-amine (188 mg, 1.409mmol) was added dropwise and the resulting reaction was stirred at RTfor 3 h. The solvent was removed and the obtained residue was washedwith EtOAc to give the title compound (200 mg, 49%) as a yellow solid.

LCMS (ESI+): m/z 435 (M+H)⁺, RT: 2.084 min.

¹H-NMR (400 MHz, MeOD): δ 7.61 (s, 1H), 7.49 (s, 1H), 7.43 (m, 1H),7.28-7.22 (m, 3H), 5.67 (t, J=7.6 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H),3.09-3.05 (m, 1H), 2.97-2.91 (m, 1H), 2.65-2.60 (m, 1H), 2.08-2.01 (m,1H), 1.88-1.77 (m, 4H), 1.29 (m, 1H), 0.84 (t, J=1.6 Hz, 6H).

Example 1362-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide 136.1 1-Bromo-4-methoxy-2-methyl-benzene

To a solution of 1-methoxy-3-methylbenzene (51.6 ml, 405 mmol) in DCM(300 mL), 1-bromopyrrolidine-2,5-dione (72.1 g, 405 mmol) was added. Theresulting reaction was stirred at about 20° C. overnight. The reactionmixture was diluted with 30-60° C. petroleum ether (200 mL). The mixturewas stirred for 30 min. The reaction mixture was filtered. The filtratewas concentrated under reduced pressure to provide the desired product(80 g, 98%) as a yellow oil, which was used in next step without furtherpurification.

136.2 1-Bromo-4-methoxy-2-methyl-5-nitro-benzene

1-Bromo-4-methoxy-2-methylbenzene obtained in step 136.1 (60 g, 298mmol) was dissolved in acetic acid (150 ml) and TFA (150 ml). Themixture was cooled to −5° C. in an ice bath. Fuming nitric acid (14.56ml, 328 mmol) was added slowly to the reaction. The resulting mixturewas stirred at −5° C. for about 2 h. The reaction mixture was dilutedwith water (100 ml). The aqueous layer was extracted with ethyl acetate(3×100 mL) and washed with sat. NaCl (100 mL), sat. NaHCO₃ (100 mL) andsat. NaCl (100 mL). The organic layer was dried with Na₂SO₄, filteredand concentrated. The resulting solid was purified with silica gelcolumn chromatography (hexane/EtOAc=50:1). The proper fractions werecollected and concentrated to give the title compound (20 g, 27%).

136.3 1-Bromo-4-methoxy-5-nitro-benzoic acid

In a 1 L round-bottomed flask,1-bromo-4-methoxy-2-methyl-5-nitro-benzene obtained in step 136.2 (70 g,0.28 mol) and KMnO₄ (270 g, 1.707 mol) were dissolved in water (500 ml)and pyridine (250 ml) and the mixture was stirred and heated to about110° C. over night. The reaction was cooled to ambient temperature andfiltered through a sintered glass funnel. The aqueous layer was adjustedto pH=2 and extracted with ethyl acetate (2×750 mL). The organic layerwas washed with sat. NaCl (300 mL), dried with Na₂SO₄, filtered andconcentrated to afford the crude title compound (60 g). This wasrecrystallized in ethanol to afford the pure title compound (38 g,48.4%).

LCMS (ESI+): m/z 263 (M+Na)⁺, RT: 1.32 min.

¹H NMR (MeOD/TMS, 400 MHz) δ: 8.09 (s, 1H), 7.64 (s, 1H), 4.00 (s, 3H).

136.4 2-(2-Carboxy-4-methoxy-5-nitro-phenyl)-malonic acid diethyl ester

To rapidly stirred diethyl malonate (58.0 g, 362 mmol) was added sodium(0.999 g, 43.5 mmol) in portions at r.t. After the addition wascomplete, the mixture was stirred at 50° C. until the sodium haddisappeared. Copper(I) bromide (0.260 g, 1.811 mmol) and then2-bromo-5-methoxy-4-nitro-benzoic acid obtained in step 136.3 (5.0 g,18.11 mmol) were added. The mixture was heated at 70° C. overnight. Thereaction mixture was dissolved in water and extracted with toluene andEtOAc. The aqueous layer was acidified with HCl (2 N). The mixture wasthen extracted with EtOAc and dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified on a silica gel column(DCM/MeOH=10:1, v/v) to afford the title compound as a yellow solid(5.02 g, 78%).

LCMS (ESI+): m/z 356 (M+H)⁺, RT: 1.56 min.

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.95 (s, 1H), 7.80 (s, 1H), 5.62 (s, 1H),4.25-4.28 (m, 4H), 4.03 (s, 3H), 1.27-1.33 (m, 6H).

136.5 2-Carboxymethyl-5-methoxy-4-nitro-benzoic acid NaOH (3.05 g, 76mmol) in water (15 mL) was added over 30 min to a solution of2-(2-carboxy-4-methoxy-5-nitro-phenyl)-malonic acid diethyl esterobtained in step 136.4 (5.42 g, 15.25 mmol) in EtOH (40 mL) at roomtemperature. The mixture was then stirred at 50° C. overnight, thesolvent was removed under reduced pressure, the contents were acidifiedwith HCl (conc.) at r.t. to pH=3 and the resulting white aqueoussuspension was extracted twice with EtOAc (100 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas dissolved in toluene (50 mL), and the mixture was heated at 105° C.The mixture was concentrated under reduced pressure and the concentratewas used in the next step without further purification.

136.6 5-Methoxy-2-methoxycarbonylmethyl-4-nitro-benzoic acid methylester

SOCl₂ (17.16 mL, 235 mmol) was added dropwise to a solution of2-carboxymethyl-5-methoxy-4-nitrobenzoic acid obtained in step 136.5(20.0 g, 78 mmol) in MeOH (150 mL) at ambient temperature. After theaddition was completed, the mixture was heated at 65° C. overnight. Themixture was concentrated in vacuo. The residue was diluted with EtOAc(200 mL) and washed with saturated aqueous NaHCO₃ (60 mL), water (60 mL)and brine (60 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified on a silica gel column(PE/EtOAc=5:1, v/v) to afford the title compound (20.7 g, 93%) as ayellow solid.

LCMS (ESI+): m/z 284 (M+H)⁺, RT: 1.95 min.

¹H NMR(CDCl₃/TMS, 400 MHz) δ: 7.72 (s, 2H), 4.01 (s, 3H), 3.97 (s, 2H),3.92 (s, 3H), 3.71 (s, 3H).

136.72-((Z)-2-Dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-4-nitro-benzoicacid methyl ester

A mixture of methyl 5-methoxy-2-methoxycarbonylmethyl-4-nitro-benzoicacid methyl ester obtained in step 136.6 (250 mg, 0.883 mmol) in DMF-DMA(5.909 ml, 44.1 mmol) was heated at 90° C. overnight. The reactionmixture was concentrated under reduced pressure. The residue was dilutedwith EtOAc (20 mL) and washed with brine (6 mL*3). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The crude oil waspure enough for next step.

LCMS (ESI+): m/z 339 (M+H)⁺, RT: 1.93 min.

136.82-Ethyl-7-methoxy-6-nitro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester

A mixture of2-((Z)-2-dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-4-nitro-benzoicacid methyl ester obtained in step 136.7 (237 mg, 0.701 mmol),ethanamine (95 mg, 2.102 mmol) and DIPEA (0.734 mL, 4.20 mmol) in MeOH(5 mL) was heated at reflux overnight. The solvent was removed underreduced pressure. The residue was diluted with EtOAc (50 mL) and washedwith HCl (2 N, 10 mL) and brine (10 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified on a silica column (PE/EtOAc=5:1, v/v) to afford the titlecompound (200 mg, 93%) as a yellow solid.

LCMS (ESI+): m/z 207 (M+H)⁺, RT: 2.05 min.

¹H NMR(CDCl₃/TMS, 400 MHz) δ: 9.24 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H),4.14 (q, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).

136.96-Amino-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester

To a suspension of2-ethyl-7-methoxy-6-nitro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester obtained in step 136.8 (200 mg, 0.653 mmol) in ethanol(10 mL) and saturated NH₄Cl solution (2 mL) was added zinc (427 mg, 6.53mmol) in one portion. The mixture was stirred at r.t. for 30 min, thenfiltered. The filtrate was concentrated in vacuo. The residue wasdiluted with EtOAc (20 mL) and washed with brine (6*2 mL). The organiclayer was dried over Na₂SO₄, filtered and concentrated to afford thetitle compound (163 mg, 90%) as a white solid.

LCMS (ESI+): m/z 277 (M+H)⁺, RT: 1.83 min.

¹H NMR (DMSO-d6/TMS, 400 MHz) δ: 8.22 (s, 1H), 7.87 (s, 1H), 7.50 (s,1H), 5.86 (br, 2H), 4.00-4.04 (q, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 1.24(t, J=7.2 Hz, 3H).

136.106-Bromo-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester

To a suspension of6-amino-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester obtained in step 136.9 (1.20 g, 4.34 mmol) in 2 NH₂SO₄ solution (25 mL) was added a solution of sodium nitrite (0.899 g,13.03 mmol) in water (5 mL) dropwise at 0° C. The mixture was stirred at0° C. for 2 h, then it was added dropwise to a solution of copper(I)bromide (2.492 g, 17.37 mmol) in HBr (48%, 5 mL). The mixture wasstirred for another 1 h at 0° C., diluted with EtOAc (100 mL) and washedwith brine (30 mL*3). The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified on a silica column(PE/EtOAc=5:1, v/v) to afford the title compound (1.31 g, 89%).

LCMS (ESI+): m/z 340 (M+H)⁺, RT: 2.04 min.

¹H NMR(CDCl₃/TMS, 400 MHz) δ: 9.02 (s, 1H), 8.01 (s, 1H), 7.76 (s, 1H),4.01-4.07 (q, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).

136.112-Ethyl-7-methoxy-4-(methoxycarbonyl)-1-oxo-1,2-dihydroisoquinolin-6-yl-boronicacid

A mixture of6-bromo-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester obtained in step 136.10 (1.31 g, 3.85 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.174 g,4.62 mmol), potassium acetate (1.134 g, 11.55 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (0.314 g, 0.385 mmol) in DMF (100 mL) wasstirred at 90° C. overnight. The mixture was diluted with EtOAc (200 mL)and washed with brine (60 mL×4). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was used in thenext step directly without further purification.

LCMS (ESI+): m/z 306 (M+H)⁺, RT: 1.82 min.

136.122-Ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester

A mixture of2-ethyl-7-methoxy-4-(methoxycarbonyl)-1-oxo-1,2-dihydroisoquinolin-6-yl-boronicacid obtained in step 136.11 (838 mg, 2.75 mmol), water (32 mL), acetone(4 mL), NaOH (110 mg, 2.75 mmol) and sodium bicarbonate (231 mg, 2.75mmol) was warmed to 50° C. for 1 h. After cooling to r.t., 30% H₂O₂(0.337 mL, 10.99 mmol) was added dropwise. The reaction was stirred atr.t. overnight, then it was acidified to pH=4 by dropwise addition of 2N HCl, and extracted with DCM (50 mL*3). The DCM layer was washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified on a silica column (PE/EtOAc=2:1, v/v) toafford the title compound (220 mg, 28.9%) as a white solid.

LCMS (ESI+): m/z 278 (M+H)⁺, RT: 1.87 min.

¹H NMR (DMSO-d6/TMS, 400 MHz) δ: 10.27 (s, 1H), 8.30 (s, 1H), 8.15 (s,1H), 7.64 (s, 1H), 4.04-4.08 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 1.26(t, J=7.2 Hz, 3H).

136.132-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester

To a solution of2-ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester of step 136.12 (50 mg, 0.180 mmol),2-(quinolin-2-yl)ethanol (31.2 mg, 0.180 mmol) and Ph₃P (142 mg, 0.541mmol) in anhydrous THF (3 mL) was added DEAD (0.086 mL, 0.541 mmol)dropwise at 0° C. The mixture was stirred at 0° C. for 30 min. Then itwas allowed to warm to ambient temperature and stirred overnight. Themixture was diluted with EtOAc (20 mL) and washed with 2 N HCl (10mL*3). The aqueous layer was basified with 2 N NaOH to pH=10, thenextracted with EtOAc (15 mL*3). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by prep-TLC(PE/EtOAc=1:1, v/v) to afford the title compound (55 mg, 47.3%).

LCMS (ESI+): m/z 433 (M+H)⁺, RT: 1.91 min.

¹H NMR(CDCl₃/TMS, 400 MHz) δ: 8.43 (s, 1H), 8.09-8.13 (m, 3H), 7.80 (s,1H), 7.65-7.70 (m, 2H), 7.47-7.51 (m, 2H), 4.69 (t, J=6.8 Hz, 2H),4.08-4.12 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.62 (t, J=6.8 Hz, 2H),1.41 (t, J=7.2 Hz, 3H).

136.142-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid

A mixture of methyl2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid ethyl ester obtained in step 136.13 (55 mg, 0.085 mmol) and NaOH(10.22 mg, 0.256 mmol) in MeOH (3 mL) and water (1 mL) was heated at 50°C. for 3 h. The reaction mixture was concentrated in vacuo. The residuewas dissolved in water (5 mL) and acidified with HCl (2 N) to pH=5˜6.The aqueous solution was extracted with EtOAc (15 mL*3). The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was used in the next step without further purification.

LCMS (ESI+): m/z 419 (M+H)⁺, RT: 2.08 min.

136.152-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

A suspension of2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid obtained in step 136.14 (80 mg, 0.080 mmol), DMF (6.22 μL, 0.080mmol) and SOCl₂ (0.018 mL, 0.241 mmol) in DCM (2 mL) was refluxed for 3h. The mixture was concentrated in vacuo. The residue was dissolved inDCM (2 mL). The solution was added dropwise to a mixture ofbutan-1-amine (11.75 mg, 0.161 mmol) and Et₃N (0.034 mL, 0.241 mmol) inDCM (2 mL) at ambient temperature. The reaction mixture was stirred atr.t. for another 3 h. Then the solvent was removed under reducedpressure, the residue was diluted with EtOAc (15 mL) and washed withbrine (5 mL*3). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified on a silica column(PE/EtOAc=1:1, v/v) to afford the title compound as a white solid (50mg), (purity 94.6% by LCMS). Further purification pre-HPLC afford thetitle compound (12 mg, 31.6%) as a white solid.

¹H NMR (CDCl₃/TMS, 400 MHz) δ: 7.35-8.17 (m, 9H), 5.88 (s, 1H), 4.65 (m,2H), 4.03-4.08 (m, 2H), 3.95 (s, 3H), 3.41-3.66 (m, 4H), 1.60-1.63 (m,2H), 1.37-1.44 (m, 5H), 0.93 (t, J=7.2 Hz, 3H).

LCMS (ESI+): m/z 474 (M+H)⁺, RT: 2.05 min.

Example 1372-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid butyl amide 137.1 (E)-3-Quinolin-2-yl-acrylic acid ethyl ester

(2-Ethoxy-2-oxoethyl)triphenylphosphonium bromide (16.8 g, 39.1 mmol)and quinoline-2-carbaldehyde (5.8 g, 36.9 mmol) were dissolved in EtOH(100 ml). The mixture was heated at about 80° C. over night. The solventwas removed under reduced pressure, and the residue was purified withsilica column (eluted with 5:1 hexane/EtOAc). The proper fractions werecollected and concentrated to give the title compound (6.8 g, 76%) asyellow oil.

LCMS (ESI+): m/z 228 (M+H)⁺, RT: 1.871 min

137.2 3-Quinolin-2-yl-propan-1-ol

To a suspension of LiA1H₄ (0.534 g, 14.05 mmol) in THF (10 ml), at −78°C. was added (E)-3-quinolin-2-yl-acrylic acid ethyl ester obtained instep 137.1 (1.6 g, 7.04 mmol) slowly. The mixture was allowed to warm toroom temperature and stirred for 3 h. Water (0.1 ml) was added slowly.The reaction mixture was filtered through a pad of celite. The solventwas removed under reduced pressure to provide the desired crude productas an off-white solid. The crude product was purified with plate TLC(eluted with 1:1 hexane/EtOAc) to give the title compound (55 mg, 4.2%).

LCMS (ESI+): m/z 188 (M+H)⁺, RT: 1.074 min.

137.32-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester

To a solution of2-ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester obtained in step 136.12 (148 mg, 0.534 mmol) and Ph₃P(420 mg, 1.602 mmol) in anhydrous THF (3 mL) was added DEAD (0.254 mL,1.602 mmol) dropwise at −30° C. The mixture was stirred at −30° C. for30 min. Then a solution of 3-quinolin-2-yl-propan-1-ol obtained in step137.2 (100 mg, 0.534 mmol) in anhydrous THF (2 mL) was added. Thereaction mixture was allowed to warm to ambient temperature and stirredovernight. The mixture was diluted with EtOAc (10 mL) and washed with 2N HCl (5 mL*3). The aqueous layer was basified with 2 N NaOH to pH=10,then extracted with EtOAc (10 mL*3). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bypre-TLC (PE/EtOAc=1:1, v/v) to afford the title compound (43 mg,11.36%).

LCMS (ESI+): m/z 447 (M+H)⁺, RT: 2.08 min.

137.42-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid

A mixture of2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid methyl ester obtained in step 137.3 (43 mg, 0.061 mmol) and sodiumhydroxide (7.28 mg, 0.182 mmol) in MeOH (3 mL) and water (1 mL) washeated at 50° C. for 3 h. The reaction mixture was acidified with HCl (2N) to pH=4˜5. The aqueous solution was concentrated in vacuo. andre-evaporated with MeOH (5 mL*3). The residue was used in the next stepwithout further purification.

LCMS (ESI+): m/z 433 (M+H)⁺, RT: 1.39 min.

137.52-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

A suspension of2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid obtained in step 137.4 (23 mg, 0.023 mmol), DMF (3.54 μL, 0.046mmol) and sulfurous dichloride (8.16 mg, 0.069 mmol) in DCM (2 mL) wasrefluxed for 3 h. The mixture was concentrated in vacuo. The residue wasdissolved in DCM (2 mL). The solution was added dropwise to a mixture ofbutan-1-amine (1.673 mg, 0.023 mmol) and Et₃N (9.56 μL, 0.069 mmol) inDCM (2 mL) at ambient temperature. The reaction mixture was stirred atr.t. for another 3 h. Then the solvent was removed under reducedpressure, the residue was diluted with EtOAc (15 mL) and washed withbrine (5 mL*3). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by pre-HPLC to affordthe title compound (3 mg, 26.9%) as a white solid.

¹H NMR (MeOD/TMS, 400 MHz) δ: 8.15 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz,1H), 7.79 (d, J=8.4 Hz, 1H), 7.61-7.64 (m, 2H), 7.52 (s, 1H), 7.49 (s,1H), 7.41-7.45 (m, 1H), 7.40 (d, J=8.4 Hz, 1H), 4.12 (t, J=5.8 Hz, 2H),3.99-4.02 (m, 2H), 3.76 (s, 3H), 3.25-3.29 (m, 2H), 3.12 (t, J=7.6 Hz,2H), 2.30 (m, 2H), 1.49-1.53 (m, 2H), 1.26-1.34 (m, 5H), 0.86 (t, J=7.4Hz, 3H).

LCMS (ESI+): m/z 488 (M+H)⁺, RT: 2.08 min.

The compounds of the following examples 138 to 166 were preparedaccording to following general procedure:

A 4 ml scintillation vial was charged with a stir bar, a solution of2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid asprepared in step 1.7 (16.57 mg, 0.059 mmol) in 1.0 mL ofN,N-dimethylacetamide (DMA), a solution of the respective amine (1.2 eq,0.0717 mmol) in DMA, a solution of HATU (27.26 mg, 0.0717 mmol, 1.2 eq)in DMA, and DIEA (3 eq, 0.179 mmol, 18.27 mg) neat. The mixture wascapped and placed in the Anton Paar Synthos 3000 optimizer at 150° C.for 30 minutes. The vial was decapped and placed to concentrate todryness. An additional 1.4 mL of DMSO/MeOH (1:1 v/v) was added fordissolution and submission for reverse phase HPLC purification.

Example 1382-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=353.9 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, 3H) 3.85-3.87 (m, 3H)3.89-3.91 (m, 3H) 4.07 (q, 1H) 7.50 (dd, J=8.39, 4.73 Hz, 1H) 7.69 (s,1H) 7.74 (s, 1H) 8.06 (s, 1H) 8.21 (d, 1H) 8.35 (s, 1H) 8.90 (s, 1H).

Example 1392-Ethyl-6,7-dimethoxy-1-oxo-N-(pyrimidin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=368.15 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.32 (t, J=7.17 Hz, 3H) 3.84 (s, 3H)3.88 (s, 3H) 4.05 (q, J=7.02 Hz, 3H) 4.57 (s, 2H) 7.56 (dd, J=5.19, 1.22Hz, 1H) 7.67 (s, 1H) 7.77 (s, 1H) 7.92 (s, 1H) 8.77 (d, J=5.19 Hz, 1H)9.13 (d, J=1.22 Hz, 1H).

Example 1402-Ethyl-6,7-dimethoxy-4-(2-methoxybenzylamino)carbonyl)isoquinolin-1(2H)-one

ESI-MS [M+H⁺]=397.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.30 (t, J=7.02 Hz, 3H) 3.83 (d,J=10.07 Hz, 6H) 3.88 (s, 3H) 4.03 (d, J=7.02 Hz, 2H) 4.46 (s, 2H) 6.96(t, 1H) 7.03 (d, 1H) 7.30 (q, 2H) 7.66 (s, 1H) 7.71 (s, 1H) 7.80 (s, 1H)

Example 1412-Ethyl-6,7-dimethoxy-N-(4-morpholinophenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=438.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 3.11-3.14 (m,4H) 3.76-3.79 (m, 4H) 3.85 (s, 3H) 3.89 (s, 3H) 4.06 (q, J=7.12 Hz, 2H)7.03 (d, J=8.85 Hz, 2H) 7.61 (d, J=8.85 Hz, 2H) 7.68 (s, 1H) 7.71 (s,1H) 7.92 (s, 1H)

Example 142N-(3-Chlorobenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=400.9 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.30 (t, J=7.02 Hz, 3H) 3.83 (s, 3H)3.88 (s, 3H) 4.03 (q, J=7.12 Hz, 2H) 4.49 (s, 2H) 7.32-7.44 (m, 4H) 7.66(s, 1H) 7.70 (s, 1H) 7.82 (s, 1H).

Example 1432-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=368.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 3.83 (s, 3H)3.88 (s, 3H) 4.03-4.10 (m, 2H) 4.69 (s, 2H) 7.67 (s, 1H) 7.75 (s, 1H)7.88 (d, J=5.80 Hz, 2H) 7.97 (s, 1H) 8.76 (s, 2H).

Example 1442-Ethyl-6,7-dimethoxy-1-oxo-N-o-tolyl-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=367.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 2.29 (s, 3H)3.85 (s, 3H) 3.89 (s, 3H) 4.07 (q, J=7.12 Hz, 2H) 7.17-7.22 (m, 1H)7.23-7.28 (m, 1H) 7.30 (d, J=7.63 Hz, 1H) 7.37-7.41 (m, 1H) 7.69 (s, 1H)7.76 (s, 1H) 8.00 (s, 1H)

Example 1452-Ethyl-6,7-dimethoxy-1-oxo-N-m-tolyl-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=367.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 2.33 (s, 3H)3.87 (d, 6H) 4.06 (q, J=7.02 Hz, 2H) 6.96 (d, J=7.63 Hz, 1H) 7.26 (t,J=7.93 Hz, 1H) 7.50 (d, J=8.24 Hz, 1H) 7.55 (s, 1H) 7.70 (d, J=14.34 Hz,2H) 7.95 (s, 1H)

Example 1462-Ethyl-6,7-dimethoxy-N-(2-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=383.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.32 (t, J=7.17 Hz, 3H) 3.84 (d,J=10.68 Hz, 6H) 3.89 (s, 3H) 4.06 (q, J=7.02 Hz, 2H) 6.97-7.02 (m, 1H)7.11 (d, J=7.32 Hz, 1H) 7.18-7.24 (m, 1H) 7.68 (s, 1H) 7.73-7.79 (m, 2H)7.96 (s, 1H)

Example 1472-Ethyl-6,7-dimethoxy-N-(3-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=383.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 3.77 (s, 3H)3.86 (s, 3H) 3.89 (s, 3H) 4.06 (q, J=7.22 Hz, 2H) 6.70-6.75 (m, 1H)7.28-7.30 (m, 2H) 7.38 (d, J=1.83 Hz, 1H) 7.69 (d, J=6.41 Hz, 2H) 7.95(s, 1H)

Example 1482-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=368.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.31 (t, J=7.02 Hz, 3H) 3.83 (s, 3H)3.88 (s, 3H) 4.04 (q, J=7.02 Hz, 2H) 4.63 (s, 2H) 7.66 (s, 1H) 7.73 (s,1H) 7.88-7.94 (m, 2H) 8.40 (d, J=7.93 Hz, 1H) 8.73 (d, J=5.19 Hz, 1H)8.83 (s, 1H)

Example 1492-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-2-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=368.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.31 (t, J=7.02 Hz, 3H) 3.83 (s, 3H)3.88 (s, 3H) 4.04 (q, J=7.02 Hz, 2H) 4.63 (s, 2H) 7.66 (s, 1H) 7.73 (s,1H) 7.88-7.94 (m, 2H) 8.40 (d, J=7.93 Hz, 1H) 8.73 (d, J=5.19 Hz, 1H)8.83 (s, 1H)

Example 150N-(3-(Dimethylamino)propyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=362.0

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.30 (t, J=7.17 Hz, 3H) 1.87-1.96 (m,2H) 2.81 (s, 6H) 3.11-3.18 (m, 2H) 3.34 (t, J=6.56 Hz, 2H) 3.87 (d,J=7.93 Hz, 6H) 4.02 (q, J=7.22 Hz, 2H) 7.66 (s, 1H) 7.74 (s, 1H) 7.77(s, 1H)

Example 1512-Ethyl-6,7-dimethoxy-1-oxo-N-phenyl-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=353.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 3.86 (s, 3H)3.89 (s, 3H) 4.06 (q, J=7.02 Hz, 2H) 7.14 (t, J=7.48 Hz, 1H) 7.37-7.41(m, 2H) 7.68-7.73 (m, 4H) 7.97 (s, 1H)

Example 1522-Ethyl-6,7-dimethoxy-N-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=397.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.29 (t, J=7.17 Hz, 3H) 3.74 (s, 3H)3.82 (s, 3H) 3.88 (s, 3H) 4.01 (q, J=7.02 Hz, 2H) 4.42 (d, J=5.80 Hz,2H) 6.91-6.95 (m, 2H) 7.31-7.34 (m, 2H) 7.65 (s, 1H) 7.70 (s, 1H) 7.75(s, 1H) 8.86 (t, J=5.80 Hz, 1H)

Example 1532-Ethyl-6,7-dimethoxy-N-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=381.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.29 (t, J=7.17 Hz, 3H) 2.31 (s, 3H)3.82 (s, 3H) 3.88 (s, 3H) 4.02 (q, J=7.22 Hz, 2H) 4.45 (d, J=5.80 Hz,2H) 7.09 (d, J=7.63 Hz, 1H) 7.16-7.21 (m, 2H) 7.23-7.28 (m, 1H) 7.66 (s,1H) 7.71 (s, 1H) 7.78 (s, 1H) 8.90 (t, J=5.95 Hz, 1H)

Example 1542-Ethyl-6,7-dimethoxy-N-(2-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=381.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.29 (t, J=7.17 Hz, 3H) 2.35 (s, 3H)3.81 (s, 3H) 3.88 (s, 3H) 4.02 (q, J=7.22 Hz, 2H) 4.47 (s, 2H) 7.18-7.22(m, 3H) 7.33 (t, J=3.51 Hz, 1H) 7.66 (s, 1H) 7.70 (s, 1H) 7.78 (s, 1H)

Example 1552-Ethyl-6,7-dimethoxy-N-(2-methoxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=335.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.29 (t, J=7.02 Hz, 3H) 3.30 (s, 3H)3.44 (t, J=5.49 Hz, 2H) 3.51 (t, J=5.80 Hz, 2H) 3.87 (d, J=7.63 Hz, 6H)4.01 (q, J=7.02 Hz, 2H) 7.65 (s, 1H) 7.72 (d, J=2.75 Hz, 2H)

Example 1562-Ethyl-N-(4-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=371.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.02 Hz, 3H) 3.86 (s, 3H)3.89 (s, 3H) 4.06 (q, J=7.22 Hz, 2H) 7.19-7.27 (m, 2H) 7.68 (s, 1H)7.71-7.75 (m, 3H) 7.97 (s, 1H)

Example 1572-Ethyl-6,7-dimethoxy-N-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=383.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 3.76 (s, 3H)3.85 (s, 3H) 3.89 (s, 3H) 4.06 (q, J=7.22 Hz, 2H) 6.96 (tt, 2H) 7.62(dt, 2H) 7.68 (s, 1H) 7.71 (s, 1H) 7.93 (s, 1H)

Example 1582-Ethyl-6,7-dimethoxy-1-oxo-N-p-tolyl-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=367.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 2.30 (s, 3H)3.85 (s, 3H) 3.89 (s, 3H) 4.06 (q, J=7.22 Hz, 2H) 7.19 (d, J=8.24 Hz,2H) 7.59 (dd, J=8.39, 2.59 Hz, 2H) 7.68 (s, 1H) 7.71 (s, 1H) 7.94 (s,1H)

Example 1592-Ethyl-N-(3-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=371.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.02 Hz, 3H) 3.86 (s, 3H)3.89 (s, 3H) 4.06 (q, J=7.02 Hz, 2H) 6.93-6.99 (m, 1H) 7.39-7.45 (m, 1H)7.46-7.50 (m, 1H) 7.66-7.72 (m, 3H) 8.00 (s, 1H)

Example 1602-Ethyl-N-(2-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=371.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.33 (t, J=7.17 Hz, 3H) 3.85 (s, 3H)3.89 (s, 3H) 4.07 (d, J=7.32 Hz, 2H) 7.22-7.35 (m, 3H) 7.66-7.72 (m, 2H)7.78 (s, 1H) 8.01 (s, 1H)

Example 1612-Ethyl-6,7-dimethoxy-N-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=381.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.29 (t, J=7.02 Hz, 3H) 2.29 (s, 3H)3.81 (s, 3H) 3.88 (s, 3H) 4.02 (q, J=7.22 Hz, 2H) 4.44 (d, J=5.19 Hz,2H) 7.17 (d, J=7.63 Hz, 2H) 7.28 (d, J=7.93 Hz, 2H) 7.65 (s, 1H) 7.70(s, 1H) 7.77 (s, 1H)

Example 162N-(2-Chlorobenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=401.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.31 (t, J=7.17 Hz, 3H) 3.82 (s, 3H)3.88 (s, 3H) 4.04 (q, J=7.22 Hz, 2H) 4.56 (d, J=5.49 Hz, 2H) 7.31-7.41(m, 2H) 7.49 (dd, J=7.78, 1.37 Hz, 2H) 7.66 (s, 1H) 7.71 (s, 1H) 7.85(s, 1H) 8.93 (t, J=5.80 Hz, 1H)

Example 163(R)-2-Ethyl-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=399.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm (t, J=7.17 Hz, 3H) 1.48 (d, J=7.32 Hz,3H) 3.79 (s, 3H) 3.87 (s, 3H) 4.04 (q, J=7.02 Hz, 2H) 5.14 (q, J=6.92Hz, 1H) 7.14-7.21 (m, 2H) 7.44-7.50 (m, 2H) 7.60 (s, 1H) 7.65 (s, 1H)7.78 (s, 1H)

Example 1642-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-4-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=353.9 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.35 (t, J=7.17 Hz, 3H) 3.88 (s, 3H)3.90 (s, 3H) 4.09 (q, J=7.02 Hz, 2H) 7.70 (s, 1H) 7.79 (s, 1H) 8.17 (d,J=7.32 Hz, 2H) 8.24 (s, 1H) 8.70 (d, J=7.32 Hz, 2H).

Example 165(S)-2-Ethyl-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=399.0 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.31 (t, J=7.17 Hz, 3H) 1.48 (d, J=7.32Hz, 3H) 3.79 (s, 3H) 3.87 (s, 3H) 4.00-4.07 (m, 2H) 5.14 (q, J=7.12 Hz,1H) 7.15-7.21 (m, 2H) 7.45-7.49 (m, 2H) 7.60 (s, 1H) 7.65 (s, 1H) 7.78(s, 1H).

Example 1662-Ethyl-6,7-dimethoxy-1-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,8a-tetrahydroisoquinoline-4-carboxamide

ESI-MS [M+H⁺]=407.2 m/z.

¹H NMR (500 MHz, DMSO/D₂O) δ ppm 1.28 (t, J=7.17 Hz, 3H) 1.75-1.88 (m,2H) 1.93-2.00 (m, 1H) 2.01-2.08 (m, 1H) 2.72-2.85 (m, 2H) 3.87 (s, 3H)3.89 (s, 3H) 4.00 (q, J=7.12 Hz, 2H) 5.24 (q, 1H) 7.13-7.16 (m, 1H)7.17-7.21 (m, 2H) 7.31-7.35 (m, 1H) 7.67 (s, 1H) 7.71 (s, 1H) 7.74 (s,1H).

The compounds of the following examples 167 to 179 were preparedaccording to following general procedure:

In a 4 ml microwave vial was added2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroiso-quinoline-4-carboxylic acidas prepared in step 1.7 (25 mg, 0.09 mmol), followed by2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU; 42 mg, 0.10 mmol),triethylamine (37 μl, 0.27 mmol) and the respective amine (0.11 mmol).This mixture was placed in Anton Par with stir bar and heated at 150° C.for 30 minutes. The crude mixture was checked via LCMS for completionand concentrated to dryness. The residue was then dissolved in 1.4 mL ofDMSO:MeOH (1:1) and purified through reverse phase HPLC (TFA methodusing MeOH) to afford pure products.

Example 1672-Ethyl-6,7-dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.02 Hz, 3H) 1.95 (dd, J=12.66, 8.09Hz, 1H) 2.29 (s, 3H) 2.74-2.85 (m, 1H) 2.90-3.02 (m, 1H) 3.88 (d, J=3.97Hz, 6H) 4.01 (q, J=7.22 Hz, 2H) 5.50 (t, J=7.78 Hz, 1H) 7.06 (d, J=7.63Hz, 1H) 7.17 (d, 2H) 7.66 (s, 1H) 7.78 (d, J=11.90 Hz, 2H).

MS (ESI+) M/Z 407 [M+H]⁺.

Example 1682-Ethyl-6,7-dimethoxy-N-(2-(morpholinomethyl)benzyl)-1-oxo-1,2-dihydroiso-quinoline-4-carboxamide

¹H NMR (500 MHz δ ppm 1.24-1.33 (m, 4H) 3.40 (d, 4H) 3.81 (s, 3H)3.87-3.89 (m, 3H) 4.04 (q, J=7.02 Hz, 4H) 4.58 (d, J=11.60 Hz, 4H) 7.43(t, J=7.48, 1.37 Hz, 1H) 7.50-7.57 (m, 2H) 7.60-7.67 (m, 3H) 7.84 (s,1H).

MS (ESI+) M/Z 466 [M+H]⁺.

Example 169N-(5-Chloro-2,3-dihydro-1H-inden-1-yl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.02 Hz, 3H) 2.00 (dd, J=12.82, 7.93Hz, 1H) 2.88 (d, J=8.24 Hz, 1H) 2.97-3.06 (m, 1H) 3.87 (d, J=6.10 Hz,6H) 4.00 (q, J=7.02 Hz, 2H) 5.50 (t, J=7.78 Hz, 1H) 7.28 (dd, J=8.09,1.98 Hz, 1H) 7.37 (t, 2H) 7.66 (s, 1H) 7.77 (d, J=3.36 Hz, 2H).

MS (ESI+) M/Z 427 [M+H]⁺.

Example 170N-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.17 Hz, 3H) 2.01 (dd, J=12.66, 8.09Hz, 1H) 2.77-2.87 (m, 1H) 2.92-3.06 (m, 1H) 3.88 (d, J=1.22 Hz, 6H) 4.01(q, J=7.02 Hz, 2H) 5.52 (t, J=7.78 Hz, 1H) 7.27-7.34 (m, 2H) 7.39 (s,1H) 7.66 (s, 1H) 7.77 (d, J=18.92 Hz, 2H).

MS (ESI+) M/Z 427 [M+H]⁺.

Example 1712-Ethyl-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.02 Hz, 3H) 1.96-2.06 (m, 1H)2.77-2.88 (m, 1H) 2.93-3.01 (m, 1H) 3.88 (d, J=4.88 Hz, 6H) 4.01 (q,J=7.02 Hz, 2H) 5.52 (t, J=7.78 Hz, 1H) 7.06 (t, 1H) 7.16 (dd, J=8.85,2.14 Hz, 1H) 7.30 (dd, J=8.24, 5.19 Hz, 1H) 7.66 (s, 1H) 7.78 (d,J=13.43 Hz, 2H).

MS (ESI+) M/Z 411 [M+H]⁺.

Example 172N-(5,6-Dihydro-4H-cyclopenta[b]thiophen-4-yl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz, Solvent) δ ppm 1.27 (t, J=7.02 Hz, 3H) 2.33-2.41 (m,1H) 2.82-2.95 (m, 2H) 3.03 (d, 1H) 3.87 (d, J=6.71 Hz, 6H) 3.99 (q,J=7.02 Hz, 2H) 5.37 (t, 1H) 6.99 (d, J=5.19 Hz, 1H) 7.39 (d, J=5.19 Hz,1H) 7.65 (s, 1H) 7.73 (d, J=13.12 Hz, 2H).

MS (ESI+) M/Z 399 [M+H]⁺.

Example 1732-Ethyl-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.17 Hz, 3H) 2.03 (dd, J=12.66, 8.39Hz, 1H) 2.79-2.96 (m, 1H) 3.04 (d, J=5.19 Hz, 1H) 3.87 (d, J=7.02 Hz,6H) 4.01 (q, J=7.02 Hz, 2H) 5.58 (d, J=7.93 Hz, 1H) 6.93-7.14 (m, 1H)7.16-7.36 (m, 2H) 7.66 (s, 1H) 7.77 (d, J=1.22 Hz, 2H) 8.78 (d, J=8.24Hz, 1H).

MS (ESI+) M/Z 411 [M+H]⁺.

Example 1742-Ethyl-6,7-dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.17 Hz, 3H) 1.96 (dd, J=12.51, 8.54Hz, 1H) 2.25 (s, 3H) 2.71-2.81 (m, 1H) 2.94 (dd, J=8.85, 3.36 Hz, 1H)3.87 (d, J=7.93 Hz, 6H) 4.00 (q, J=7.12 Hz, 2H) 5.54 (t, J=7.78 Hz, 1H)7.07 (d, J=7.32 Hz, 1H) 7.10-7.24 (m, 2H) 7.66 (s, 1H) 7.76 (d, J=14.34Hz, 2H).

MS (ESI+) M/Z 407 [M+H]⁺.

Example 1752-Ethyl-6,7-dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.27 (t, J=7.17 Hz, 3H) 1.89-2.02 (m, 1H) 2.30(s, 3H) 2.76-2.87 (m, 1H) 2.91-3.01 (m, 1H) 3.87 (d, J=7.63 Hz, 6H) 4.00(q, J=7.12 Hz, 2H) 5.48 (t, J=7.63 Hz, 1H) 6.98-7.14 (m, 2H) 7.25 (d,J=7.63 Hz, 1H) 7.66 (s, 1H) 7.76 (d, J=15.56 Hz, 2H).

MS (ESI+) M/Z 407 [M+H]⁺.

Example 1762-Ethyl-6,7-dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.17 Hz, 3H) 1.97 (dd, J=12.51, 7.93Hz, 1H) 2.70-2.85 (m, 1H) 2.91 (dd, J=8.85, 3.36 Hz, 1H) 3.72 (s, 3H)3.87 (d, J=9.76 Hz, 6H) 4.01 (q, J=7.02 Hz, 2H) 5.49 (t, J=7.93 Hz, 1H)6.82 (dd, J=7.93, 2.14 Hz, 1H) 6.92 (d, J=2.14 Hz, 1H) 7.19 (d, J=8.24Hz, 1H) 7.66 (s, 1H) 7.78 (d, J=5.80 Hz, 2H).

MS (ESI+) M/Z 423 [M+H]⁺.

Example 1772-Ethyl-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.28 (t, J=7.17 Hz, 3H) 2.01 (dd, J=12.51, 7.93Hz, 1H) 2.76-2.93 (m, 1H) 2.96-3.13 (m, 1H) 3.87 (d, J=6.10 Hz, 6H) 4.00(q, J=7.02 Hz, 2H) 5.50 (d, J=7.63 Hz, 1H) 6.95-7.19 (m, 2H) 7.38 (dd,J=8.09, 5.34 Hz, 1H) 7.66 (s, 1H) 7.77 (d, J=6.10 Hz, 2H) 8.73 (d,J=8.24 Hz, 1H).

MS (ESI+) M/Z 411 [M+H]⁺.

Example 178N-(2-((Diethylamino)methyl)benzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.18-1.45 (m, 9H) 3.25 (q, 4H) 3.79 (s, 3H) 3.87(s, 3H) 4.04 (q, J=7.02 Hz, 2H) 4.53 (d, J=14.04 Hz, 4H) 7.43 (t,J=7.48, 1.37 Hz, 1H) 7.50-7.57 (m, 2H) 7.59 (t, 2H) 7.65 (s, 1H) 7.85(s, 1H).

MS (ESI+) M/Z 452 [M+H]⁺.

Example 1792-Ethyl-6,7-dimethoxy-1-oxo-N-(2-(pyrrolidin-1-ylmethyl)benzyl)-1,2-dihydroisoquinoline-4-carboxamide

¹H NMR (500 MHz) δ ppm 1.22-1.34 (m, 4H) 1.89-1.97 (m, 2H) 2.08-2.16 (m,2H) 3.19-3.26 (m, 2H) 3.47-3.55 (m, 2H) 3.80 (s, 3H) 3.86-3.89 (m, 4H)3.97-4.07 (m, 2H) 4.58 (d, J=3.36 Hz, 4H) 7.41 (t, 1H) 7.49-7.58 (m, 3H)7.65 (d, 2H) 7.83 (s, 1H).

MS (ESI+) M/Z 450 [M+H]⁺.

The compounds of the following examples 180 and 181 were prepared byanalogy to example 133 starting from2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-2-carboxylicacid, which in turn was prepared by analogy to steps 133.1-133.7 ofexample 133 starting from commercially available5-bromo-2-methoxy-isonicotinic acid.

Example 1802-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acidindan-1-ylamide

ESI-MS: [M+Na⁺]=386.20, [M+H⁺]=364.10.

Example 1812-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acidbutylamide

ESI-MS: [M+Na⁺]=629.20, [M+H⁺]=304.10.

The compound of the following example 182 was prepared according toexample 133 starting from (Z)-methyl2-(1-(dimethylamino)-3-methoxy-3-oxoprop-1-en-2-yl)-5-methoxybenzoate,which in turn was prepared according to step 133.6 of example 133starting from starting from 2-(quinolin-2-yl)ethanamine.

Example 1827-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide

ESI-MS: [M+H⁺]=430.20.

The following compounds were prepared in analogy to the above examples.

Example 183

7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide

ESI-MS: [M+H⁺]=490.20.

Example 184(S)-3-ethyl-6,7-dimethoxy-4-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-3,4-dihydrophthalazine-1-carboxamide

ESI-MS: [M+Na⁺]=430.20, [M+H⁺]=408.20.

Example 1853-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(S)-indan-1-ylamide

ESI-MS: [M+Na⁺]=416.20, [M+H⁺]=394.20.

Example 1862-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

ESI-MS: [M+H⁺]=436.20.

Example 1872-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 2-dimethylaminomethyl-benzylamide hydrochloride

ESI-MS: [M+H⁺]=466.30.

Example 1882-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3,5-difluoro-benzylamide

ESI-MS: [M+H⁺]=445.20;

Example 1892-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3,4-difluoro-benzylamide

ESI-MS: [M+H⁺]=445.20.

Example 1902-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid cyclohexylmethyl-amide

ESI-MS: [M+H⁺]=415.30;

Example 1912-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (R)-indan-1-ylamide

ESI-MS: [M+H⁺]=435.30.

Example 1922-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (S)-indan-1-ylamide

ESI-MS: [M+H⁺]=435.30.

Example 1932-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide

ESI-MS: 442.10, [M+H⁺]=441.10.

Example 1942-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (2,3-dihydro-benzofuran-3-yl)-amide

ESI-MS: [M+Na⁺]=459.15, 438.20, [M+H⁺]=437.15.

Example 1952-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide

ESI-MS: [M+Na⁺]=477.05, 456.10, [M+H⁺]=455.10.

Example 1962-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide

ESI-MS: 406.10, [M+H⁺]=405.10.

Example 1972-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide

ESI-MS: 422.15, [M+H⁺]=421.10.

Example 1982-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide

ESI-MS: 408.20, [M+H⁺]=407.15;

Example 199(+)-2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

ESI-MS: 437.20, [M+H⁺]=436.20.

Example 200(−)-2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

ESI-MS: 437.20, [M+H⁺]=436.20.

Example 2012-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid ([1,3,4]thiadiazol-2-ylmethyl)-amide

ESI-MS: 418.20, [M+H⁺]=417.10.

Example 2022-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 2-(morpholine-4-sulfonyl)-benzylamide

ESI-MS: 560.20, 559.20, [M+H⁺]=558.20;

Example 2032-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (thiazol-4-ylmethyl)-amide

ESI-MS: 417.10, [M+H⁺]=416.10.

Example 204(+)-2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide

ESI-MS: [M+H⁺]=399.10.

Example 205(−)-2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide

ESI-MS: [M+H⁺]=399.10.

Example 2062-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (thiophen-3-ylmethyl)-amide

ESI-MS: 416.10, [M+H⁺]=415.10.

Example 2072-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-piperidine-1-carbonyl)-2H-isoquinolin-1-one

ESI-MS: [M+H⁺]=463.10.

Example 2082-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine-1-carbonyl)-2H-isoquinolin-1-one

ESI-MS: [M+H⁺]=479.20.

Example 2092-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-piperazine-1-carbonyl]-2H-isoquinolin-1-one

ESI-MS: [M+H⁺]=494.20.

Example 2102-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one

ESI-MS: [M+H⁺]=597.20.

Example 2112-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one

ESI-MS: [M+H⁺]=584.20.

Example 2122-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperazine-1-carbonyl]-2H-isoquinolin-1-one

ESI-MS: [M+H⁺]=508.30.

Example 2132-(1-Ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidine-1-carbonyl]-2H-isoquinolin-1-one

ESI-MS: [M+H]⁺=517.20.

Example 2144-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7-dimethoxy-2H-isoquinolin-1-onetrifluoroacetate

ESI-MS: [M+H]⁺=450.20.

Example 2152-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3-(4-chloro-benzenesulfonylamino)-benzylamide

ESI-MS: [M]⁺=598.20.

Example 2162-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide

ESI-MS: [M+Na]⁺=475.20, [M+H⁺]=453.20.

Example 2172-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide

ESI-MS: [M+Na]⁺=434.10, [M+H⁺]=412.10.

Example 2182-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (S)-indan-1-ylamide

ESI-MS: [M+Na]⁺=428.10, [M+H⁺]=406.20.

Example 2192-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide

ESI-MS: [M+H]⁺=571.30.

Example 2202-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid 2-(morpholine-4-sulfonyl)-benzylamide

ESI-MS: [M+Na]⁺=551.20, [M+H]⁺=529.20.

Example 2212-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

ESI-MS: [M+Na]⁺=429.15, [M+H]⁺=407.20.

Example 2222-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3-(4-methoxy-benzenesulfonylamino)-benzylamide

ESI-MS: [M+Na]⁺=616.20, [M+H]⁺=594.30.

Example 2232-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid 3,5-difluoro-benzylamide

ESI-MS: [M+Na]⁺=438.15, [M+H]⁺=416.10

Example 2242-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid 4-methyl-benzylamide

ESI-MS: [M+Na]⁺=416.20, [M+H]⁺=394.20.

Example 2252-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid cyclohexylmethyl-amide

ESI-MS: [M+Na]⁺=408.20, [M+H]⁺=386.20.

Example 2262-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid butylamide

ESI-MS: [M+H]⁺=346.20.

Example 2272-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (2,3-dihydro-benzofuran-3-yl)-amide

ESI-MS: [M+Na]⁺=430.20, [M+H]⁺=408.20.

Example 2282-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (thiazol-2-ylmethyl)-amide

ESI-MS: [M+Na]⁺=438.10, [M+H]⁺=416.10.

Example 2292-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (thiophen-2-ylmethyl)-amide

ESI-MS: [M+Na]⁺=437.10, [M+H]⁺=415.10.

Example 2302-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide

ESI-MS: [M+Na]⁺=392.10, [M+H]⁺=370.10.

Example 2313-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide trifluoroacetate

ESI-MS: [M+Na]⁺=464.10, [M+H]⁺=442.15.

Example 2323-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid (2,3-dihydro-benzofuran-3-yl)-amide trifluoroacetate

ESI-MS: [M+Na]⁺=460.20, [M+H]⁺=438.20.

Example 2333-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

ESI-MS: [M+Na⁺]=459.20, [M+H]⁺=437.20.

Example 2342-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin-1-one

ESI-MS: [M+Na]⁺=430.20, [M+H]⁺=408.20

Example 2353-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid indan-1-ylamide

ESI-MS: [M+Na]⁺=458.20, [M+H]⁺=436.20.

Example 2366,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

A microwave vial was charged with a stir bar and 284 mg of PS-TFP (10eq.). To the vessel were added6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxylicacid (29 mg, 0.09 mmol) dissolved in dry THF (1.0 mL) and CCl₃CN (36 μL,0.36 mmol) dissolved in dry THF (0.5 mL). The reaction vessel was sealedand heated to 120° C. for 1800 seconds. Then pyridin-3-ylmethanamine (15mg, 0.135 mmol) dissolved in THF (0.5 mL) was added followed by DIEA (47μL, 0.27 mmol). The mixture was heated again to 150° C. for 1800seconds. After cooling the reaction mixture was filtered and productswere collected and concentrated to dryness. The residues were dissolvedin 1:1 DMSO/MeOH. Purification by reverse phase HPLC provided the titlecompound (14.7 mg, 31%).

ESI-MS=410 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 8.86 (s, 1H) 8.76 (d, J=5.49Hz, 1H) 8.47 (d, J=7.93 Hz, 1H) 7.97 (dd, J=7.93, 5.49 Hz, 1H) 7.74 (s,1H) 7.67 (d, J=10.99 Hz, 2H) 4.86 (s, 1H) 4.65 (s, 2H) 3.86 (d, J=28.08Hz, 6H) 1.69-1.90 (m, 4H) 0.74 (t, J=7.32 Hz, 6H).

The following compounds of examples 237 to 244 were prepared in ananalogous manner to the process described in example 236.

Example 2376,7-Dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=429 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.72 (s, 1H) 7.67 (s, 1H)7.50 (s, 1H) 6.83 (d, J=3.36 Hz, 1H) 6.65 (d, J=2.14 Hz, 1H) 4.85 (s,1H) 4.55 (s, 2H) 3.86 (d, J=21.36 Hz, 6H) 2.39 (s, 3H) 1.65-1.85 (m, 4H)0.72 (t, J=7.32 Hz, 6H).

Example 238N-((3,5-Dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=428[M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.67 (s, 1H) 7.63 (s, 1H)7.45 (s, 1H) 4.83 (s, 1H) 4.26 (s, 2H) 3.85 (d, J=28.99 Hz, 6H) 2.43 (s,3H) 2.26 (s, 3H) 1.65-1.85 (m, 4H) 0.72 (t, J=7.17 Hz, 6H).

Example 2396,7-Dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=430 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.80 (s, 1H) 7.69 (s, 1H)7.60 (s, 1H) 7.42 (s, 1H) 4.87 (s, 1H) 4.68 (s, 2H) 3.88 (d, J=14.04 Hz,6H) 2.42 (s, 3H) 1.68-1.88 (m, 4H) 0.74 (t, J=7.32 Hz, 6H).

Example 2406,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=411 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 9.13 (s, 1H) 8.76-8.79 (m,1H) 7.77-7.81 (m, 1H) 7.67-7.70 (m, 2H) 7.55 (d, J=4.88 Hz, 1H) 4.87 (s,1H) 4.56-4.61 (m, 2H) 3.89 (s, 3H) 3.84 (s, 3H) 1.77-1.86 (m, 4H) 0.75(t, J=7.32 Hz, 6H).

Example 2416,7-Dimethoxy-N-((3-methylisoxazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=414 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.75 (s, 1H) 7.68 (s, 1H)7.58 (s, 1H) 6.30 (s, 1H) 4.85 (s, 1H) 4.57 (s, 2H) 3.87 (d, J=16.48 Hz,6H) 2.22 (s, 3H) 1.71-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).

Example 242N-((2,5-dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=443 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.67 (s, 1H) 7.63 (s, 1H)7.47 (s, 1H) 6.69 (s, 1H) 4.84 (s, 1H) 4.30 (s, 2H) 3.85 (d, J=30.21 Hz,6H) 2.31-2.39 (m, 6H) 1.67-1.84 (m, 4H) 0.72 (t, J=7.32 Hz, 6H).

Example 2436,7-Dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=430 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.73 (s, 1H) 7.67 (s, 1H)7.58 (s, 1H) 7.51 (s, 1H) 4.84 (s, 2H) 4.60 (s, 2H) 3.87 (d, 6H) 2.62(s, 3H) 1.66-1.85 (m, 4H) 0.72 (t, J=7.32 Hz, 6H).

Example 2446,7-Dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=414 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.78 (s, 1H) 7.68 (s, 1H)7.55-7.59 (m, 1H) 6.25 (s, 1H) 4.85 (s, 1H) 4.48 (s, 2H) 3.87 (d,J=10.38 Hz, 6H) 2.39 (s, 3H) 1.70-1.85 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).

Example 245(R)—N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

The title compound was prepared in analogy to the process described inexample 236 but using (R)-1-(4-fluorophenyl)ethanamine instead ofpyridine-3-ylmethanamine.

ESI-MS=441 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.67 (s, 1H) 7.43-7.53 (m,4H) 7.19 (t, J=8.85 Hz, 2H) 5.17 (q, J=6.92 Hz, 1H) 4.84 (s, 1H) 3.83(d, J=50.35 Hz, 6H) 1.67-1.88 (m, 4H) 1.50 (d, J=7.32 Hz, 3H) 0.69-0.78(m, 6H).

Example 246(S)—N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

The title compound was prepared in analogy to the process described inexample 236 but using (S)-1-(4-fluorophenyl)ethanamine instead ofpyridine-3-ylmethanamine.

ESI-MS=441 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.67 (s, 1H) 7.42-7.55 (m,4H) 7.19 (t, J=8.85 Hz, 2H) 5.17 (q, J=7.02 Hz, 1H) 4.84 (s, 1H) 3.83(d, J=50.35 Hz, 6H) 1.67-1.90 (m, 4H) 1.50 (d, J=7.32 Hz, 3H) 0.68-0.78(m, 6H).

The compounds of examples 247 to 269 were prepared in an analogousmanner to the process described in example 236.

Example 2476,7-Dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=430 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.78 (s, 1H) 7.69 (s, 1H)7.62 (s, 1H) 7.20 (s, 1H) 4.81-4.94 (m, J=10.38 Hz, 1H) 4.72 (s, 2H)3.87 (d, J=19.53 Hz, 6H) 2.36 (s, 3H) 1.68-1.87 (m, 4H) 0.74 (t, J=7.32Hz, 6H).

Example 248

6,7-Dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=430 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.75 (s, 1H) 7.68 (s, 1H)7.60 (s, 1H) 7.32 (s, 1H) 4.85 (s, 1H) 4.53 (s, 2H) 3.86 (d, J=20.45 Hz,6H) 2.66 (s, 3H) 1.67-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).

Example 2496,7-Dimethoxy-N-((4-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=430[M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 8.96 (s, 1H) 7.68 (d, J=8.54Hz, 2H) 7.50 (s, 1H) 4.85 (s, 1H) 4.61 (s, 2H) 3.86 (d, J=22.28 Hz, 6H)2.45 (s, 3H) 1.67-1.89 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).

Example 2506,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=467 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.72 (s, 1H) 7.68 (s, 1H)7.56 (s, 1H) 7.17 (d, J=2.14 Hz, 1H) 6.58 (d, J=3.05 Hz, 1H) 4.85 (s,1H) 4.56 (s, 2H) 3.86 (d, 6H) 1.67-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).

Example 2516,7-Dimethoxy-N-((5-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=413 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.73 (s, 1H) 7.67 (s, 1H)7.53 (s, 1H) 6.21 (d, J=2.75 Hz, 1H) 6.03 (d, J=2.14 Hz, 1H) 4.85 (s,1H) 4.42 (s, 2H) 3.86 (d, J=20.14 Hz, 6H) 2.24 (s, 3H) 1.66-1.87 (m, 4H)0.73 (t, J=7.32 Hz, 6H).

Example 252N-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS [M+H]⁺=453 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.73 (s, 1H) 7.68 (s, 1H)7.52 (s, 1H) 7.38 (dd, J=8.24, 5.49 Hz, 1H) 7.10-7.13 (m, 1H) 7.02-7.07(m, 1H) 5.53 (t, J=7.78 Hz, 1H) 4.83 (s, 1H) 3.87 (d, J=11.90 Hz, 6H)2.96-3.05 (m, 1H) 2.81-2.92 (m, 1H) 2.54-2.59 (m, 1H) 1.96-2.10 (m, 1H)1.65-1.86 (m, 4H) 0.73 (q, J=7.02 Hz, 6H).

Example 2536,7-Dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=449 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.73 (s, 1H) 7.68 (s, 1H)7.50 (s, 1H) 7.24 (d, J=7.63 Hz, 1H) 7.10 (s, 1H) 7.05 (d, J=7.63 Hz,1H) 5.52 (t, J=7.78 Hz, 1H) 4.83 (s, 1H) 3.87 (d, J=14.34 Hz, 6H)2.92-3.02 (m, 1H) 2.77-2.89 (m, 1H) 2.46-2.51 (m, 1H) 2.30 (s, 3H)1.91-2.03 (m, 1H) 1.65-1.85 (m, 4H) 0.73 (q, J=7.02 Hz, 6H).

Example 2546,7-Dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=449 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.74 (s, 1H) 7.68 (s, 1H)7.51 (s, 1H) 7.12-7.21 (m, 2H) 7.07 (d, J=7.32 Hz, 1H) 5.57 (t, J=7.93Hz, 1H) 4.84 (s, 1H) 3.87 (d, J=14.34 Hz, 6H) 2.90-3.02 (m, 1H)2.72-2.83 (m, 1H) 2.55-2.59 (m, 1H) 2.25 (s, 3H) 1.92-2.04 (m, 1H)1.66-1.83 (m, 4H) 0.68-0.77 (m, 6H).

Example 255N-((2-Ethylthiazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=444 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.75 (s, 1H) 7.68 (s, 1H)7.60 (s, 1H) 7.33 (s, 1H) 4.86 (s, 1H) 4.54 (s, 2H) 3.86 (d, J=21.06 Hz,6H) 2.98 (q, J=7.53 Hz, 2H) 1.70-1.86 (m, 4H) 1.30 (t, J=7.48 Hz, 3H)0.73 (t, J=7.32 Hz, 6H).

Example 2566,7-Dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=465 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.75 (s, 1H) 7.68 (s, 1H)7.54 (s, 1H) 7.20 (d, J=8.24 Hz, 1H) 6.90 (d, J=1.83 Hz, 1H) 6.83 (dd,J=8.24, 2.44 Hz, 1H) 5.52 (t, J=7.93 Hz, 1H) 4.84 (s, 1H) 3.87 (d,J=16.17 Hz, 6H) 3.72 (s, 3H) 2.89-2.99 (m, 1H) 2.74-2.83 (m, 1H)2.47-2.52 (m, 1H) 1.95-2.04 (m, 1H) 1.67-1.85 (m, 4H) 0.73 (q, J=7.02Hz, 6H).

Example 2576,7-Dimethoxy-N-((4-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=429 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.72 (s, 1H) 7.67 (s, 1H)7.51 (s, 1H) 6.97 (s, 1H) 6.88 (s, 1H) 4.85 (s, 1H) 4.58 (s, 2H)3.80-3.90 (m, 6H) 2.16-2.19 (m, 3H) 1.66-1.87 (m, 4H) 0.73 (t, J=7.32Hz, 6H).

Example 2586,7-Dimethoxy-N-((3-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=429 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.68 (d, J=6.10 Hz, 2H)7.46-7.51 (m, 1H) 7.30 (d, J=4.88 Hz, 1H) 6.86 (d, J=4.88 Hz, 1H) 4.85(s, 1H) 4.57 (s, 2H) 3.79-3.91 (m, 6H) 2.24 (s, 3H) 1.63-1.86 (m, 4H)0.73 (t, J=7.32 Hz, 6H).

Example 2596,7-Dimethoxy-N-((5-methyloxazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=414 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.81 (s, 1H) 7.68 (s, 1H)7.60 (s, 1H) 6.79 (d, J=1.22 Hz, 1H) 4.86 (s, 1H) 4.54 (s, 2H) 3.88 (d,J=10.38 Hz, 6H) 2.28 (s, 3H) 1.66-1.88 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).

Example 2606,7-Dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=449 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.74 (s, 1H) 7.69 (s, 1H)7.52 (s, 1H) 7.14-7.20 (m, 2H) 7.06 (d, J=7.93 Hz, 1H) 5.54 (t, J=7.93Hz, 1H) 4.84 (s, 1H) 3.88 (d, J=11.29 Hz, 6H) 2.88-3.01 (m, 1H)2.74-2.87 (m, 1H) 2.46-2.51 (m, 1H) 2.28 (s, 3H) 1.92-2.01 (m, 1H)1.66-1.85 (m, 4H) 0.73 (q, J=7.63 Hz, 6H).

Example 2616,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=410 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 8.81 (d, J=6.71 Hz, 2H) 7.96(d, J=6.41 Hz, 2H) 7.77 (s, 1H) 7.73 (s, 1H) 7.69 (s, 1H) 4.80-4.95 (m,J=6.10 Hz, 1H) 4.73 (s, 2H) 3.84 (d, 6H) 1.70-1.89 (m, 4H) 0.75 (t,J=7.32 Hz, 6H).

Example 2626,7-Dimethoxy-N-(4-methylbenzyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=423 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.69 (d, J=10.99 Hz, 2H)7.54 (s, 1H) 7.27 (d, J=7.93 Hz, 2H) 7.18 (d, J=7.93 Hz, 2H) 4.85 (s,1H) 4.45 (s, 2H) 3.85 (d, 6H) 2.29 (s, 3H) 1.67-1.87 (m, 4H) 0.73 (t,J=7.32 Hz, 6H).

Example 2636,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=410 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 8.73 (d, J=4.88 Hz, 1H)8.28-8.34 (m, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.78 (s, 1H) 7.72-7.76 (m, 2H)7.69 (s, 1H) 4.88 (s, 1H) 4.74 (s, 2H) 3.85 (d, J=31.43 Hz, 6H)1.68-1.92 (m, 4H) 0.75 (t, J=7.32 Hz, 6H).

Example 264N-((5-Cyanofuran-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=424 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.71 (s, 1H) 7.68 (s, 1H)7.57 (s, 1H) 7.54 (d, J=3.66 Hz, 1H) 6.64 (d, J=3.66 Hz, 1H) 4.84 (s,1H) 4.56 (s, 2H) 3.87 (d, J=14.04 Hz, 6H) 1.67-1.89 (m, J=12.82 Hz, 4H)0.73 (t, J=7.32 Hz, 6H).

Example 265N-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=469 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.67-7.74 (m, J=17.70 Hz,2H) 7.52 (s, 1H) 7.25-7.37 (m, 3H) 5.64 (q, J=7.93 Hz, 1H) 4.83 (s, 1H)3.87 (d, J=10.68 Hz, 6H) 3.00-3.10 (m, 1H) 2.83-2.95 (m, 1H) 2.55-2.62(m, 1H) 1.97-2.12 (m, 1H) 1.64-1.86 (m, 4H) 0.67-0.79 (m, 6H).

Example 266N-((5-Ethylthiophen-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=443 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.72 (s, 1H) 7.67 (s, 1H)7.51 (s, 1H) 6.85 (d, J=3.36 Hz, 1H) 6.68 (d, J=3.36 Hz, 1H) 4.84 (s,1H) 4.57 (s, 2H) 3.86 (d, J=16.78 Hz, 6H) 2.76 (q, J=7.43 Hz, 2H)1.64-1.90 (m, 4H) 1.21 (t, J=7.63 Hz, 3H) 0.73 (t, J=7.32 Hz, 6H).

Example 2676,7-Dimethoxy-N-((3-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=413 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.68 (d, J=8.24 Hz, 2H)7.44-7.52 (m, 2H) 6.32 (d, J=1.83 Hz, 1H) 4.83 (s, 1H) 4.45 (s, 2H) 3.85(d, J=18.62 Hz, 6H) 2.06 (s, 3H) 1.65-1.85 (m, 4H) 0.72 (t, J=7.32 Hz,6H).

Example 2686,7-Dimethoxy-N-((2-methylfuran-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=413 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂ 0, T: 27° C.) δ ppm 7.67 (s, 2H) 7.42-7.48 (m,2H) 6.44 (d, J=1.53 Hz, 1H) 4.83 (s, 1H) 4.25 (s, 2H) 3.85 (d, J=19.84Hz, 6H) 2.30 (s, 3H) 1.59-1.89 (m, 4H) 0.72 (t, J=7.32 Hz, 6H).

Example 2696,7-Dimethoxy-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS=413 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.75 (s, 1H) 7.68 (s, 1H)7.62 (d, J=2.14 Hz, 1H) 7.55 (s, 1H) 6.22 (d, J=2.14 Hz, 1H) 4.84 (s,1H) 4.43 (s, 2H) 3.87 (d, J=14.04 Hz, 6H) 3.80 (s, 3H) 1.65-1.86 (m, 4H)0.73 (t, J=7.17 Hz, 6H).

Example 270N-[(3,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

To a solution of2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid(25 mg, 0.09 mmol) in DMA (1.0 mL) was added a solution of HATU (41 mg,0.1 mmol) in DMA (0.5 mL). The reaction mixture was placed to shake for45 minutes at room temperature. Then a solution of(3,4-dimethylphenyl)methanamine (18 mg, 0.13 mmol) dissolved in DMA (0.4mL) was added followed by triethylamine neat (40 μL, 0.27 mmol). Thereaction was shaken at 65° C. overnight. The reaction was checked byLC/MS and concentrated to dryness. The residues were dissolved in 1:1DMSO/MeOH. Purification by reverse phase HPLC provided the titledcompound (17.9 mg, 50%)

ESI-MS: m/z 395 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.75 (s, 1H) 7.70 (s, 1H)7.65 (s, 1H) 7.15 (s, 1H) 7.11 (s, 2H) 4.41 (s, 2H) 4.02 (q, J=7.12 Hz,2H) 3.88 (s, 3H) 3.81 (s, 3H) 2.21 (d, J=6.10 Hz, 6H) 1.29 (t, J=7.17Hz, 3H).

The compounds of examples 271 to 292 were prepared in analogy to theprocess described in example 270.

Example 271N-[(2-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 415 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.81 (s, 1H) 7.71 (s, 1H)7.66 (s, 1H) 7.36 (d, J=7.63 Hz, 1H) 7.31 (s, 1H) 7.18 (d, J=8.24 Hz,1H) 4.51 (s, 2H) 4.03 (q, J=7.12 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.30(s, 3H) 1.30 (t, J=7.17 Hz, 3H).

Example 272N-[[2-(Dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 424 [M+H]⁺.

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 8.75 (t, J=5.80 Hz, 1H) 7.78(s, 1H) 7.75 (s, 1H) 7.66 (s, 1H) 7.22 (d, J=7.63 Hz, 1H) 6.96 (s, 1H)6.87 (d, J=7.93 Hz, 1H) 4.53 (d, J=5.49 Hz, 2H) 4.02 (q, J=7.22 Hz, 2H)3.88 (s, 3H) 3.81-3.85 (m, 3H) 2.66 (s, 6H) 2.28 (s, 3H) 1.29 (t, J=7.17Hz, 3H);

Example 2732-Ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 399 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 8.86 (t, J=5.65 Hz, 1H) 7.77(s, 1H) 7.69 (s, 1H) 7.65 (s, 1H) 7.34 (t, J=8.09 Hz, 1H) 7.01-7.06 (m,2H) 4.43-4.50 (m, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H)2.31 (s, 3H) 1.29 (t, J=7.17 Hz, 3H).

Example 2742-Ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 411 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.77 (s, 1H) 7.71 (s, 1H)7.66 (s, 1H) 7.11 (d, J=7.93 Hz, 1H) 6.95 (s, 1H) 6.84-6.90 (m, 1H) 4.45(s, 2H) 4.02 (q, J=7.12 Hz, 2H) 3.88 (s, 3H) 3.81 (s, 3H) 3.78 (s, 3H)2.13 (s, 3H) 1.29 (t, J=7.17 Hz, 3H).

Example 2752-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 466 [M+H]⁺.

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.76 (d, J=7.02 Hz, 2H)7.65-7.68 (m, 1H) 7.26 (d, J=7.63 Hz, 1H) 6.97 (s, 1H) 6.94 (d, J=7.93Hz, 1H) 4.55 (s, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.84 (s, 3H)3.75-3.79 (m, J=4.27 Hz, 4H) 2.83-2.90 (m, 4H) 2.29 (s, 3H) 1.29 (t,3H).

Example 276N-[(2-tert-Butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 453 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.76 (s, 1H) 7.72 (s, 1H)7.66 (s, 1H) 7.22 (d, J=7.93 Hz, 1H) 6.91 (s, 1H) 6.86 (d, J=7.63 Hz,1H) 4.45 (s, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.83 (s, 3H) 2.28(s, 3H) 1.38 (s, 9H) 1.29 (t, J=7.17 Hz, 3H).

Example 277N-[[2-(1,1-Dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 467 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.77 (s, 1H) 7.73 (s, 1H)7.66 (s, 1H) 7.20 (d, J=7.93 Hz, 1H) 6.88 (s, 1H) 6.84 (d, J=7.63 Hz,1H) 4.44 (s, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.83 (s, 3H) 2.28(s, 3H) 1.75 (q, J=7.63 Hz, 2H) 1.32 (s, 6H) 1.29 (t, J=7.17 Hz, 3H)0.97 (t, J=7.32 Hz, 3H).

Example 278N-[(2,3-Difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 417 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.78 (s, 1H) 7.69 (s, 1H)7.65 (s, 1H) 7.17 (t, J=7.93 Hz, 1H) 7.11 (t, J=7.32 Hz, 1H) 4.51 (s,2H) 3.98-4.07 (m, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.27 (d, J=1.83 Hz, 3H)1.30 (t, 3H).

Example 2792-Ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 399 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.80 (s, 1H) 7.70 (s, 1H)7.66 (s, 1H) 7.27 (t, J=8.09 Hz, 1H) 7.10-7.15 (m, 2H) 4.45 (s, 2H) 4.03(q, J=7.12 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.22 (d, J=1.22 Hz, 3H)1.29 (t, J=7.02 Hz, 3H).

Example 280N-[(3-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 413 [M+H]⁻

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.79 (s, 1H) 7.69 (s, 1H)7.66 (s, 1H) 7.41 (d, J=1.53 Hz, 1H) 7.32-7.36 (m, 1H) 7.24-7.28 (m, 1H)4.44 (s, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.31 (s,3H) 1.30 (t, 3H).

Example 2812-Ethyl-6,7-dimethoxy-1-oxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline-4-carboxamide

ESI-MS: m/z 409 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.64 (s, 2H) 7.61 (s, 1H)6.87 (s, 2H) 4.47 (s, 2H) 3.97 (q, J=7.12 Hz, 2H) 3.87 (s, 3H) 3.80 (s,3H) 2.33-2.36 (m, 6H) 2.22 (s, 3H) 1.25 (t, J=7.02 Hz, 3H).

Example 282N-[(2,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 395 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.74 (s, 1H) 7.69 (s, 1H)7.65 (s, 1H) 7.21 (d, J=7.63 Hz, 1H) 6.98-7.03 (m, 2H) 4.43 (s, 2H)3.95-4.06 (m, 2H) 3.88 (s, 3H) 3.80-3.82 (m, 3H) 2.31 (s, 3H) 2.26 (s,3H) 1.29 (t, J=7.17 Hz, 3H).

Example 2832-Ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 469 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.76 (s, 1H) 7.72 (s, 1H)7.66 (s, 1H) 7.17 (d, J=7.63 Hz, 1H) 6.83 (s, 1H) 6.75 (d, J=7.63 Hz,1H) 4.42 (s, 2H) 3.97-4.07 (m, 4H) 3.88 (s, 3H) 3.81 (s, 3H) 3.50 (t,J=6.26 Hz, 2H) 3.20 (s, 3H) 2.29 (s, 3H) 1.93-2.03 (m, 2H) 1.29 (t,J=7.17 Hz, 3H).

Example 284N-[[2-(2-Ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 469 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.76 (s, 1H) 7.69 (s, 1H)7.66 (s, 1H) 7.18 (d, J=7.63 Hz, 1H) 6.86 (s, 1H) 6.77 (d, J=7.63 Hz,1H) 4.43 (s, 2H) 4.10-4.15 (m, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88 (s, 3H)3.81 (s, 3H) 3.74 (s, 2H) 3.48 (q, J=7.02 Hz, 2H) 2.29 (s, 3H) 1.29 (t,J=7.02 Hz, 3H) 1.05 (t, J=7.02 Hz, 3H).

Example 285N-[[2-(Cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 465 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.74 (d, J=4.58 Hz, 2H) 7.66(s, 1H) 7.15 (d, J=7.63 Hz, 1H) 6.81 (s, 1H) 6.73 (d, J=7.63 Hz, 1H)4.82-4.90 (m, 1H) 4.38 (s, 2H) 4.01 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82(s, 3H) 2.29 (s, 3H) 1.82-1.97 (m, 2H) 1.64-1.81 (m, 4H) 1.50-1.64 (m,2H) 1.29 (t, J=7.17 Hz, 3H).

Example 2862-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 473 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.70 (s, 1H) 7.64 (d, J=3.36Hz, 2H) 7.35-7.42 (m, 3H) 7.11 (t, J=7.32 Hz, 1H) 6.95-7.05 (m, 3H) 6.73(s, 1H) 4.45 (s, 2H) 3.97 (q, J=7.12 Hz, 2H) 3.87 (s, 3H) 3.80 (s, 3H)2.26 (s, 3H) 1.27 (t, J=7.02 Hz, 3H).

Example 287

2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxy-1-methyl-ethoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 469 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.75 (s, 1H) 7.70 (s, 1H)7.66 (s, 1H) 7.17 (d, J=7.63 Hz, 1H) 6.88 (s, 1H) 6.75 (d, J=7.32 Hz,1H) 4.57-4.67 (m, 1H) 4.33-4.49 (m, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s,3H) 3.81 (s, 3H) 3.42-3.55 (m, 2H) 3.23 (s, 3H) 2.29 (s, 3H) 1.22-1.34(m, 6H).

Example 2882-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 479 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.78 (s, 1H) 7.73 (s, 1H)7.66 (s, 1H) 7.23 (d, J=7.63 Hz, 1H) 6.96 (s, 1H) 6.88 (d, J=7.32 Hz,1H) 4.75 (q, J=8.65 Hz, 2H) 4.44 (s, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88(s, 3H) 3.83 (s, 3H) 2.31 (s, 3H) 1.29 (t, J=7.17 Hz, 3H).

Example 289N-[[2-(Cyclohexyloxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 479 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.76 (d, J=6.10 Hz, 2H) 7.66(s, 1H) 7.16 (d, J=7.93 Hz, 1H) 6.84 (s, 1H) 6.73 (d, J=7.63 Hz, 1H)4.37-4.46 (m, 3H) 4.01 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H)2.25-2.31 (m, 3H) 1.83-1.93 (m, J=7.93, 3.97 Hz, 2H) 1.64-1.76 (m, 2H)1.44-1.58 (m, 3H) 1.32-1.45 (m, 2H) 1.29 (t, J=7.17 Hz, 4H).

Example 290N-[[2-(Cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 451 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.79 (s, 1H) 7.73 (s, 1H)7.66 (s, 1H) 7.17 (d, J=7.63 Hz, 1H) 6.81 (s, 1H) 6.75 (d, J=7.02 Hz,1H) 4.44 (s, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.85-3.90 (m, 5H) 3.82 (s, 3H)2.28 (s, 3H) 1.19-1.35 (m, 4H) 0.51-0.61 (m, 2H) 0.31-0.37 (m, 2H).

Example 2912-Ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 481 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.77 (s, 1H) 7.74 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.82 (s, 1H) 6.74 (d, J=7.63 Hz,1H) 4.41 (s, 2H) 3.92-4.09 (m, 4H) 3.88 (s, 3H) 3.81 (s, 3H) 2.29 (s,3H) 1.66-1.76 (m, 2H) 1.36-1.49 (m, 2H) 1.15-1.34 (m, 7H) 0.81 (t, 3H).

Example 2922-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3-ylmethoxy)phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 481 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 27° C.) δ ppm 7.77 (s, 1H) 7.73 (s, 1H)7.66 (s, 1H) 7.17 (d, J=7.63 Hz, 1H) 6.85 (s, 1H) 6.76 (d, J=7.93 Hz,1H) 4.42 (s, 2H) 3.96-4.08 (m, 3H) 3.89-3.95 (m, 1H) 3.88 (s, 3H) 3.81(s, 3H) 3.76-3.80 (m, 2H) 3.62-3.69 (m, 1H) 3.55-3.62 (m, J=8.54, 5.49Hz, 1H) 2.62-2.75 (m, 1H) 2.29 (s, 3H) 1.98-2.10 (m, 1H) 1.66-1.76 (m,1H) 1.29 (t, J=7.17 Hz, 3H).

Example 2932-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide

2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid(22 mg, 0.08 mmol) dissolved in N,N-dimethylacetamide (1.0 mL) was addedto a 4 mL vial charged with a stir bar followed by a solution of HATU(36 mg, 0.09 mmol) dissolved in N,N-dimethylacetamide (1.0 mL). This wasplaced to shake for one hour at room temperature. Then a solution of(2-(2-methoxyethoxy)-4-methylphenyl)methanamine (19.5 mg, 0.1 mmol)dissolved in N,N-dimethylacetamide (0.4 mL) was added followed bytriethylamine neat (33 μL, 0.24 mmol) and the mixture was stirred andheated at 65° C. overnight. The reaction was controlled by LC/MS andconcentrated to dryness. The residue was dissolved in 1:1 MeOH:DMSO.Purification by reverse phase HPLC gave 16.5 mg of the title compound(46%).

ESI-MS: m/z 455 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.77 (s, 1H) 7.70 (s, 1H)7.66 (s, 1H) 7.18 (d, J=7.63 Hz, 1H) 6.85 (s, 1H) 6.77 (d, J=7.63 Hz,1H) 4.39-4.45 (m, 2H) 4.11-4.17 (m, 2H) 4.02 (q, J=7.12 Hz, 2H) 3.88 (s,3H) 3.81 (s, 3H) 3.67-3.71 (m, 2H) 3.27 (s, 3H) 2.29 (s, 3H) 1.29 (t,J=7.02 Hz, 3H).

The compounds of the following examples 294 to 323 were prepared inanalogy to the processes described in the examples above.

Example 2942-Ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 453 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.78 (s, 1H) 7.74 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.81 (s, 1H) 6.75 (d, J=7.63 Hz,1H) 4.42-4.46 (m, 2H) 4.01 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H)3.78 (d, J=6.41 Hz, 2H) 2.29 (s, 3H) 2.00-2.12 (m, 1H) 1.29 (t, J=7.02Hz, 3H) 1.00 (d, J=6.71 Hz, 6H).

Example 2952-Ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 477 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.77 (s, 1H) 7.71 (s, 1H)7.65 (s, 2H) 7.19 (d, J=7.63 Hz, 1H) 7.01 (s, 1H) 6.80 (d, J=7.63 Hz,1H) 6.60 (d, J=3.05 Hz, 1H) 6.42-6.51 (m, 1H) 5.11 (s, 2H) 4.35-4.43 (m,2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.81 (s, 3H) 2.31 (s, 3H) 1.29(t, J=7.02 Hz, 3H).

Example 2962-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 467 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.78 (s, 1H) 7.74 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.82 (s, 1H) 6.74 (d, J=7.63 Hz,1H) 4.40-4.44 (m, 2H) 3.96-4.06 (m, 4H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29(s, 3H) 1.68-1.77 (m, 2H) 1.36-1.46 (m, 2H) 1.26-1.34 (m, 5H) 0.83 (t,J=7.17 Hz, 3H).

Example 297N-(2-Ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 425 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.77 (s, 1H) 7.72 (s, 1H)7.66 (s, 1H) 7.17 (d, J=7.63 Hz, 1H) 6.82 (s, 1H) 6.75 (d, J=7.32 Hz,1H) 4.39-4.45 (m, 2H) 3.98-4.10 (m, 4H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29(s, 3H) 1.35 (t, J=6.87 Hz, 3H) 1.29 (t, J=7.17 Hz, 3H).

Example 298N-(2-sec-Butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 453 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.76 (s, 1H) 7.74 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.83 (s, 1H) 6.73 (d, J=7.63 Hz,1H) 4.38-4.47 (m, 3H) 4.01 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H)2.29 (s, 3H) 1.56-1.76 (m, 2H) 1.29 (t, J=7.17 Hz, 3H) 1.25 (d, J=6.10Hz, 3H) 0.93 (t, J=7.32 Hz, 3H).

Example 2992-Ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 467 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.78 (s, 1H) 7.74 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.84 (s, 1H) 6.75 (d, J=7.63 Hz,1H) 4.38-4.44 (m, 2H) 4.01 (q, J=6.82 Hz, 4H) 3.88 (s, 3H) 3.82 (s, 3H)2.29 (s, 3H) 1.75-1.86 (m, 1H) 1.64 (q, J=6.41 Hz, 2H) 1.29 (t, J=7.17Hz, 3H) 0.90 (d, J=6.71 Hz, 6H).

Example 3002-Ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 439 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.77 (s, 1H) 7.73 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.82 (s, 1H) 6.75 (d, J=7.63 Hz,1H) 4.43 (s, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.96 (t, J=6.26 Hz, 2H) 3.88(s, 3H) 3.82 (s, 3H) 2.29 (s, 3H) 1.69-1.84 (m, 2H) 1.29 (t, J=7.02 Hz,3H) 1.00 (t, J=7.32 Hz, 3H).

Example 3012-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 427 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.80 (s, 1H) 7.73 (s, 1H)7.66 (s, 1H) 7.23 (d, J=7.63 Hz, 1H) 7.13 (s, 1H) 7.00 (d, J=7.93 Hz,1H) 4.45 (s, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.49(s, 3H) 2.31 (s, 3H) 1.30 (t, J=7.02 Hz, 3H).

Example 3022-Ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 439 [M+H]⁺

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.76 (s, 1H) 7.73 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.84 (s, 1H) 6.73 (d, J=7.93 Hz,1H) 4.56-4.68 (m, 1H) 4.40 (s, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H)3.82 (s, 3H) 2.29 (s, 3H) 1.24-1.34 (m, 9H).

Example 3032-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 467 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.75 (s, 1H) 7.73 (s, 1H)7.65 (s, 1H) 7.19 (d, J=7.63 Hz, 1H) 6.82 (s, 1H) 6.77 (d, J=7.63 Hz,1H) 5.07 (dd, J=5.80, 4.58 Hz, 1H) 4.39 (s, 2H) 4.01 (q, J=7.02 Hz, 2H)3.73-3.95 (m, 10H) 2.30 (s, 3H) 2.16-2.27 (m, 1H) 2.03 (dd, J=12.51,6.10 Hz, 1H) 1.29 (t, J=7.17 Hz, 3H).

Example 3042-Ethyl-6,7-dimethoxy-1-oxo-N-(2,4,5-trimethylbenzyl)-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 409 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.73 (s, 1H) 7.69 (s, 1H)7.65 (s, 1H) 7.07 (s, 1H) 6.96 (s, 1H) 4.40 (s, 2H) 4.01 (q, J=7.22 Hz,2H) 3.88 (s, 3H) 3.80 (s, 3H) 2.27 (s, 3H) 2.17 (s, 6H) 1.28 (t, J=7.17Hz, 3H).

Example 3052-Ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2-yl)methoxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 481 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.77 (s, 1H) 7.70 (s, 1H)7.65 (s, 1H) 7.17 (d, J=7.63 Hz, 1H) 6.85 (s, 1H) 6.77 (d, J=7.32 Hz,1H) 4.42 (s, 2H) 4.16-4.24 (m, 1H) 3.98-4.06 (m, 3H) 3.92-3.97 (m, 1H)3.88 (s, 3H) 3.81 (s, 3H) 3.67-3.71 (m, 1H) 3.59-3.67 (m, 1H) 2.29 (s,3H) 1.95-2.05 (m, 1H) 1.68-1.93 (m, 3H) 1.29 (t, J=7.17 Hz, 3H).

Example 3062-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 481 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.76 (s, 1H) 7.75 (s, 1H)7.66 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.84 (s, 1H) 6.72 (d, J=7.32 Hz,1H) 4.50-4.58 (m, 1H) 4.39 (s, 2H) 3.96-4.06 (m, 2H) 3.88 (s, 3H) 3.82(s, 3H) 2.29 (s, 3H) 1.70-1.82 (m, 1H) 1.61-1.70 (m, 1H) 1.34-1.44 (m,1H) 1.29 (t, J=7.02 Hz, 3H) 1.24 (d, J=5.80 Hz, 3H) 0.87 (dd, J=8.54,6.71 Hz, 6H).

Example 3072-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 481 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.78 (s, 1H) 7.75 (s, 1H)7.65 (s, 1H) 7.16 (d, J=7.63 Hz, 1H) 6.82 (s, 1H) 6.74 (d, J=7.32 Hz,1H) 4.41 (s, 2H) 3.94-4.06 (m, 4H) 3.88 (s, 3H) 3.81 (s, 3H) 2.25-2.31(m, 3H) 1.66-1.80 (m, 2H) 1.47-1.60 (m, 1H) 1.26-1.34 (m, 5H) 0.83 (d,J=6.71 Hz, 6H).

Example 3082-Ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

ESI-MS: m/z 411 [M+H]⁺;

¹H NMR (500 MHz, DMSO-D₂O, T: 25° C.) δ ppm 7.77 (s, 1H) 7.71 (s, 1H)7.66 (s, 1H) 7.17 (d, J=7.63 Hz, 1H) 6.84 (s, 1H) 6.76 (d, J=7.32 Hz,1H) 4.40 (s, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 6H) 2.30(s, 3H) 1.29 (t, J=7.17 Hz, 3H).

Example 3092-Ethyl-6,7-dimethoxy-1-oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxamide

ESI-MS: m/z 374.1 [M+H]⁺

Example 3102-Ethyl-6,7-dimethoxy-1-oxo-N-[[4-(trifluoromethyl)phenyl]-methyl]isoquinoline-4-carboxamide

¹H NMR (DMSO-d₆, 600 MHz): δ=8.99 (br. s., 1H), 7.89 (s, 1H), 7.78 (s,1H), 7.73 (m, 2H), 7.63 (m, 3H), 4.57 (br. S., 2H), 4.03 (m, 2H), 3.87(s, 3H), 3.81 (s, 3H), 1.27-1.32 (m, 3H).

Example 3112-Ethyl-6,7-dimethoxy-1-oxo-N-[(1S)-1-(p-tolyl)ethyl]isoquinoline-4-carboxamide

ESI-MS: m/z 395.2 [M+H]⁺

Example 3122-Ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 409.2 [M+H]⁺

Example 3132-Ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 395.2 [M+H]⁺

Example 3142-Ethyl-6,7-dimethoxy-1-oxo-N-[(1R)-1-(p-tolyl)ethyl]isoquinoline-4-carboxamide

ESI-MS: m/z 395.2 [M+H]⁺

Example 315N-[[4-(Difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 417.1 [M+H]⁺

Example 3162-Ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 388.1 [M+H]⁺

Example 3172-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 387.1 [M+H]⁺

Example 318N-[(4-Cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 407.2 [M+H]⁺

Example 319N-Indan-1-yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 484.20 [M+H]⁺

Example 320N-Butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide

ESI-MS: m/z 424.20 [M+H]⁺

Example 3212-Ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide;2,2,2-trifluoroacetic acid

ESI-MS: m/z 412.10 [M+H]⁺

Example 322N-Butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-carboxamide;2,2,2-trifluoroacetic acid

ESI-MS: m/z 460.20 [M+H]⁺

Example 323N-Indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-carboxamide;2,2,2-trifluoroacetic acid

ESI-MS: m/z 520.20 [M+H]⁺

Biological Tests a) Measurement of PDE Activity

The recombinant PDE proteins are used in in vitro enzymatic reaction formeasurement of PDE activity. These recombinant proteins, includingPDE10A (human, rat and mouse PDE10) and isoforms of PDEs 1, 3, 4, and 5,were purchased from commercial vendor BPS Bioscience. The enzymaticactivity of PDEs was determined by cAMP measurement kit from CisBio(IBA) using HTRF technology.

The PDE enzymatic reaction was carried out in assay buffer (20 mMTris-HCl pH7.5, 10 mM MgCl₂, 0.1% bovine serum albumin) containingenzyme and substrate. The PDE enzymes concentration ranged from 10 pM250 pM, depending on each enzyme's specific activity. The substratecyclic nucleotide (cAMP or cGMP) concentration used in the assay was 20nM for PDE10, and 100 nM for other PDEs. The inhibitory effect ofcompound was determined by incubating various concentration of inhibitorin the enzymatic assay. Typically, compound was serial diluted in DMSOthen further diluted in assay buffer. Next, the compound at varyingconcentration was mixed with PDE enzyme. The reaction was initiated byaddition of cyclic nucleotide substrate, and incubated for 60 minutes at29 C. The reaction was stopped by addition of lysis buffer from assaykit. The cAMP-d2 and anti-cAMP cryptate in the lysis buffer detected thelevel of cAMP left from the PDE hydrolysis reaction. The PDE activity isreversely correlated with the amount of cAMP left in the reaction andcan be converted to the percent activity of an uninhibited control(100%). Thus, IC₅₀ value of inhibitor can be obtained by plottinginhibitor concentration against PDE activity at that concentration. Theresults are shown in Table 1.

TABLE 1 Example IC₅₀ ¹⁾ 1 ++ 15 + 20 + 21 + 23 + 24 + 26 ++ 28 + 29 +30 + 31 + 32 + 33 + 34 + 35 + 36 ++ 37 ++ 39 ++ 40 ++ 51 + 129 +++ 135+++ 136 +++ 139 + 140 + 141 ++ 142 ++ 145 + 146 + 147 ++ 148 + 149 +151 + 152 + 153 ++ 154 ++ 156 + 158 ++ 161 +++ 162 + 164 + 165 ++ 167 +168 + 169 + 171 + 172 ++ 173 + 174 + 175 + 176 + 177 + 182 ++ 186 ++187 + 188 ++ 189 ++ 190 ++ 191 + 192 +++ 193 +++ 194 +++ 195 ++ 197 ++198 + 199 + 200 + 201 + 202 +++ 205 + 216 +++ 219 +++ 228 ++ 230 ++ 233++ 236 ++ 237 ++ 238 ++ 239 ++ 241 ++ 242 + 244 + 246 ++ 247 ++ 248 ++249 + 251 ++ 252 ++ 253 +++ 254 +++ 255 + 256 +++ 257 ++ 258 ++ 259 +260 ++ 261 + 262 ++ 263 ++ 264 + 265 + 266 + 267 ++ 268 + 269 + 273 +276 + 277 + 278 + 288 + 290 + 293 + 298 + 302 + 303 + 305 + 308 + 309 +311 + 313 + 316 + 317 ++ 318 + 322 +++ 323 + ¹⁾+++: IC₅₀ <100 nM ++: 100nM ≦ IC₅₀ ≦ 200 nM +: 200 nM < IC₅₀ < 500 nM

b) Determination of the Microsomal Half-Life:

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances were incubated in a concentration of 0.5 μM asfollows:

0.5 μM test substance are preincubated together with liver microsomesfrom different species (from rat, human or other species) (0.25 mg ofmicrosomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 inmicrotiter plates at 37° C. for 5 min. The reaction is started by addingNADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl aliquots areremoved, and the reaction is immediately stopped and cooled with thesame volume of acetonitrile. The samples are frozen until analyzed. Theremaining concentration of undegraded test substance is determined byMSMS. The half-life (T½) is determined from the gradient of the signalof test substance/unit time plot, it being possible to calculate thehalf-life of the test substance, assuming first order kinetics, from thedecrease in the concentration of the compound with time. The microsomalclearance (mCl) is calculated from mCl=ln 2/T½/(content of microsomalprotein in mg/ml)×1000 [ml/min/mg] (modified from references: Di, TheSociety for Biomoleculur Screening, 2003, 453-462; Obach, D M D, 1999vol 27. N 11, 1350-1359). The results are shown in Table 2.

TABLE 2 Rat mCl²⁾ Human mCl²⁾ Ex. [μl min⁻¹ mg⁻¹] [μl min⁻¹ mg⁻¹] 40 ++++ 136 ∘ + 141 ++ ++ 147 ++ ++ 158 ++ ++ 161 ++ ++ 165 ++ ++ 171 ++ ++172 ++ ++ 186 ++ ++ 190 + ∘ 192 + ∘ 195 + + 196 ++ ++ 197 + ∘ 198 ++ +199 ++ ++ 200 ++ ++ 201 ++ ++ 202 + ∘ 203 ++ ++ 204 ++ + 205 ++ ++219 + + 228 ++ ++ 236 ++ + 238 + ++ 239 + + 241 + ++ 244 ++ ++ 246 + ∘247 ++ + 248 ++ + 251 ∘ + 256 + ∘ 263 ++ ++ 267 ∘ + 309 nd ++ 310 ++ ++311 nd ++ 312 ++ + 313 ++ ++ 314 ++ ++ 315 ++ ++ 316 ++ ++ 317 + ++ 318++ ++ Ex. Example mCl mikrosomal clearance ²⁾++: <100 μl min⁻¹ mg⁻¹ +:100-220 μl min⁻¹ mg⁻¹ ∘: >220 μl min⁻¹ mg⁻¹ nd: not determined

1. A compound of formula (I)

wherein X¹ is CH or N; X² is C—R⁵ or N; Y is O or S; R¹ is selected fromthe group consisting of C₂-C₈-alkyl, C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl,C₃-C₈-cycloalkyl, C₅-C₈-cycloalkyl carrying a fused benzene ring,fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinatedC₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)) and a moiety L¹-Ar¹; R²is a radical of the formula CR²¹R²²R²³, where R²¹ is selected from thegroup consisting of hydrogen, C₁-C₈-alkyl, trimethylsilyl,C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl, fluorinatedC₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinatedC₃-C₈-cycloalkyl-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₁-C₄-alkyl-N(R^(b))(R^(c)), (CH₂)_(m)C(O)O—R^(d),(CH₂)_(m)C(O)N(R^(e))(R^(f)) and Z²—Ar², R²² is selected from the groupconsisting of hydrogen, fluorine, C₁-C₈-alkyl, C₂-C₈-alkenyl,C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl andC₁-C₄-alkyl-N(R^(b))(R^(c)), or R²¹ and R²² together with the carbonatom, to which they are bound form a saturated 5- to 7-memberedcarbocyclic ring or a saturated 5- to 7-membered heterocyclic ring whichhas 1, 2 or 3 heteroatoms or heteroatom containing groups selected fromthe group consisting of O, N, S, SO and SO₂ as ring members, where thecarbocyclic ring and the heterocyclic ring may be unsubstituted or maybe substituted by 1, 2 or 3 identical or different substituents R^(g),and where the carbocyclic ring and the heterocyclic ring may carry afused benzene ring or a fused 5- or 6-membered heteroaromatic ring,where the fused rings themselves are unsubstituted or carry 1, 2 or 3substituents R^(h), R²³ is selected from the group consisting ofhydrogen, fluorine, C₁-C₈-alkyl and C₁-C₄-fluoroalkyl; R³ is selectedfrom the group consisting of hydrogen, C₁-C₈-alkyl, C₂-C₈-alkenyl,C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,C₁-C₄-alkyl-N(R^(b))(R^(c)), and trimethylsilyl, or R² and R³ togetherwith the nitrogen atom, to which they are bound form a saturated 5- to7-membered heterocyclic ring which, in addition to the nitrogen atom,may have 1 or 2 further heteroatoms or heteroatom containing groupsselected from the group consisting of O, N, S, SO and SO₂ as ringmembers, where the heterocyclic ring may be unsubstituted or may besubstituted by 1, 2 or 3 identical or different substituents R³¹, andwhere the heterocyclic ring may carry a fused benzene ring or a fused 5-or 6-membered heteroaromatic ring, where the fused rings themselves areunsubstituted or carry 1, 2 or 3 substituents R³², where R³¹ is selectedfrom the group consisting of halogen, CN, OH, C₁-C₄-alkyl, fluorinatedC₁-C₄-alkyl, C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy, N(R^(b))(R^(c)),C(O)O—R^(d), and C(O)N(R^(e))(R^(f)), where one radical R³¹ may also bea moiety Z³—Ar³; and R³² is selected from the group consisting ofhalogen, CN, OH, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy,fluorinated C₁-C₄-alkoxy, N(R^(b))(R^(c)), C(O)O—R^(d) andC(O)N(R^(e))(R^(f)); R⁴ is selected from the group consisting ofC₁-C₄-alkyl, C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-C₁-C₄-alkyl and Z⁴—Ar⁴, R⁵ is selected from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-fluoroalkyl,C₁-C₄-alkoxy, C₁-C₄-fluoroalkoxy, —Z⁵—Ar⁵, —O—Z⁵—Ar⁵, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-C₁-C₄-alkyl, C₃-C₆-cycloalkoxy andC₃-C₆-cycloalkyl-C₁-C₄-alkoxy, where the cyclic radical in the last fourmentioned groups may be unsubstituted, partially or completelyfluorinated or carries 1, 2, 3 or 4 methyl groups; Ar¹ is selected fromthe group consisting of phenyl, monocyclic 5- or 6-membered hetaryl orbicyclic 9- or 10-membered hetaryl, where hetaryl has 1, 2 or 3heteroatoms as ring members which are selected from the group consistingof O, S and N, where phenyl and hetaryl are unsubstituted or may carry1, 2 or 3 identical or different substituents R^(h); Ar² is phenyl,where phenyl may carry 1, 2 or 3 identical or different substituentsR^(h); Ar³ is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2or 3 heteroatoms as ring members which are selected from the groupconsisting of O, S and N, where phenyl and monocyclic hetaryl areunsubstituted or may carry 1, 2 or 3 identical or different substituentsR^(h); Ar⁴ and Ar⁵ are independently of each other selected from thegroup consisting of phenyl and monocyclic 5- or 6-membered hetarylhaving 1, 2 or 3 heteroatoms as ring members which are selected from thegroup consisting of O, S and N, where phenyl and monocyclic hetaryl areunsubstituted or may carry 1, 2 or 3 identical or different substituentsR^(k); Z¹, Z⁴, and Z⁵ are independently of each other C₁-C₄-alkylene; Z²is a single bond or C₁-C₄-alkylene; Z³ is a single bond, C₁-C₄-alkylene,O, N, S, SO or SO₂; R^(a) is selected from the group consisting ofhalogen, CN, OH, NO₂, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl,C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy, (CH₂)_(m)N(R^(b))(R^(c)),C(O)O—R^(d), C(O)N(R^(e))(R^(f)), N(R^(ee))S(O)₂(R^(ff)) andS(O)₂N(R^(e))(R^(f)); R^(b), and R^(c), independently of each other areselected from the group consisting of hydrogen, C₁-C₄-alkyl,C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and benzylor R^(b) and R^(c) form together with the N atom to which they areattached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or3 further different or identical heteroatoms or heteroatom containinggroups selected from the group of O, N, S, SO and SO₂ as ring membersand which may carry 1, 2, 3, 4, 5 or 6 substituents selected fromC₁-C₄-alkyl; R^(d) is selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and benzyl;R^(e), and R^(f), independently of each other are selected from thegroup consisting of hydrogen, C₁-C₄-alkyl, C₁-C₄-fluoroalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and benzyl or R^(e) and R^(f)form together with the N atom to which they are attached a 3- to7-membered, nitrogen heterocycle which may have 1, 2 or 3 furtherdifferent or identical heteroatoms or heteroatom containing groupsselected from the group consisting of O, N, S, SO and SO₂ as ringmembers and which may carry 1, 2, 3, 4, 5 or 6 substituents selectedfrom C₁-C₄-alkyl; R^(g) is selected from the group consisting ofhalogen, CN, OH, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₄-fluoroalkyl,C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-C₁-C₄-alkyl, fluorinated C₃-C₆-cycloalkyl-C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,C₁-C₄-alkyl-N(R^(b))(R^(c)), C₁-C₄-alkoxy, and fluorinated C₁-C₄-alkoxy,where one R^(g) together with a carbon atom to which R^(g) is attachedmay also form a carbonyl group, where one R^(g) may also be phenyl orbenzyl, where the phenyl ring in the last 2 mentioned radicals isunsubstituted or carries 1, 2 or 3 radicals R^(h); R^(h) is selectedfrom the group consisting of halogen, CN, OH, C₁-C₄-alkyl, fluorinatedC₁-C₄-alkyl, C₁-C₆-alkoxy, fluorinated C₁-C₄-alkoxy,C₁-C₄-alkylsulfanyl, C₁-C₄-alkoxy-C₁-C₄-alkoxy, C₃-C₆-cycloalkyl,fluorinated C₃-C₆-cycloalkyl, C₃-C₆-cycloalkoxy,C₃-C₆-cycloalkyl-C₁-C₄-alkoxy, phenoxy, N(R^(b))(R^(c)),C₁-C₄-alkyl-N(R^(b))(R^(c)), C(O)O—R^(d), C(O)N(R^(e))(R^(f)),N(R^(ee))S(O)₂(R^(ff)), S(O)₂N(R^(e))(R^(f)), 3- to 7-memberedheterocyclyloxy, 3- to 7-membered heterocyclyl-C₁-C₄-alkoxy, whereheterocyclyl in the two last mentioned radicals has 1, 2 or 3heteroatoms as ring members which are selected from the group consistingof O, S and N, and 5- to 6-membered hetaryl-C₁-C₄-alkoxy, where hetarylhas 1, 2 or 3 heteroatoms as ring members which are selected from thegroup consisting of O, S and N; R^(k) is selected from the groupconsisting of halogen, CN, OH, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl,C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy, N(R^(b))(R^(c)), C(O)O—R^(d),C(O)N(R^(e))(R^(f)), N(R^(ee))S(O)₂(R^(ff)) and S(O)₂N(R^(e))(R^(f)) ortwo radicals R^(k) that are bound to adjacent carbon atoms together withsaid carbon atoms may form fused benzene ring or a fused 5- or6-membered heteroaromatic ring having 1 or 2 ring members selected fromthe group consisting of O, N and S, where the fused benzene ring and thefused heteroaromatic ring are unsubstituted or may carry 1, 2 or 3radicals R^(h); R^(ee) is selected from the group consisting ofhydrogen, C₁-C₄-alkyl, C₁-C₄-fluoroalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl and benzyl; R^(ff) is selected from the groupconsisting of C₁-C₄-alkyl, C₁-C₄-fluoroalkyl and phenyl, which isunsubstituted or carries 1, 2 or 3 radicals R^(h); and m is 0, 1, 2, 3or 4; or an N-oxide, hydrate, or tautomer thereof, or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, where R^(h) isselected from the group consisting of halogen, CN, OH, C₁-C₄-alkyl,fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy, fluorinated C₁-C₄-alkoxy,C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl, N(R^(b))(R^(c)),C₁-C₄-alkyl-N(R^(b))(R^(c)), C(O)O—R^(d), C(O)N(R^(e))(R^(f)),N(R^(ee))S(O)₂(R^(ff)) and S(O)₂N(R^(e))(R^(f)).
 3. The compound ofclaim 1, where X¹ is C—H.
 4. The compound of claim 1, where X¹ is N. 5.The compound of claim 1, where X² is C—R⁵.
 6. The compound of claim 1,where X² is N.
 7. The compound of claim 1, where Y is O.
 8. The compoundof claim 1, where R¹ is C₂-C₈-alkyl, C₃-C₈-cycloalkyl orC₃-C₈-cycloalkylmethyl.
 9. The compound of claim 8, where R¹ is aradical of the formula CHR^(1a)R^(1b), where R^(1a) is selected from thegroup consisting of hydrogen and C₁-C₃-alkyl and where R¹b is selectedfrom the group consisting of C₁-C₄-alkyl.
 10. The compound of claim 1,where R¹ is a moiety Z¹—Ar¹.
 11. (canceled)
 12. The compound of claim 1,where R²¹ and R²² together with the carbon atom, to which they are boundform a saturated 5- to 7-membered carbocyclic ring or a saturated 5- to7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms orheteroatom containing groups selected from the group of O, N, S, SO andSO₂ as ring members, where the carbocyclic ring and the heterocyclicring may be unsubstituted or may be substituted by 1, 2 or 3 identicalor different substituents R^(g), and where the carbocyclic ring and theheterocyclic ring may carry a fused benzene ring or a fused 5- or6-membered heteroaromatic ring, where the fused rings themselves areunsubstituted or carry 1, 2 or 3 substituents R^(h), and where R²³ ishydrogen.
 13. The compound of claim 1, where R²¹ and R²² together withthe carbon atom, to which they are bound form a saturated 5- to7-membered carbocyclic ring or a 3-tetrahydrofuryl or3-tetrahydrothienyl, where the 5- to 7-membered carbocyclic ring and the3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fused benzene ringor a fused 5- or 6-membered heteroaromatic ring, where the fused ringsthemselves are unsubstituted or carry 1, 2 or 3 substituents, and whereR²³ is hydrogen.
 14. The compound of claim 1, where R²¹ is selected fromthe group consisting of C₁-C₈-alkyl, trimethylsilyl, C₂-C₈-alkenyl,C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyland Z²—Ar²; R²² is selected from the group consisting of hydrogen,fluorine, and C₁-C₈-alkyl; and R²³ is hydrogen.
 15. The compound ofclaim 14, where R²¹ is a moiety Z²—Ar².
 16. The compound of claim 1,where R³ is hydrogen or C₁-C₄-alkyl.
 17. The compound of claim 1, whereR² and R³ together with the nitrogen atom, to which they are bound forma saturated 5- to 7-membered heterocyclic ring which, in addition to thenitrogen atom, may have 1 or 2 further heteroatoms or heteroatomcontaining groups selected from the group consisting of O, N, S, SO andSO₂ as ring members, where the heterocyclic ring may be unsubstituted ormay be substituted by 1, 2 or 3 identical or different substituents R³¹,and where the heterocyclic ring may carry a fused benzene ring or afused 5- or 6-membered heteroaromatic ring, where the fused ringsthemselves are unsubstituted or carry 1, 2 or 3 substituents R³². 18.The compound of claim 1, where R is C₁-C₄-alkyl.
 19. The compound ofclaim 1, where X² is C—R³ and R⁵ is hydrogen, fluorine, C₁-C₄-alkoxy ora radical O—Z⁵—Ar⁵.
 20. The compound of claim 19, where R⁴ is methyl andR⁵ is hydrogen, fluorine or methoxy.
 21. The compound of claim 19, whereis methyl and R⁵ is O—Z⁵—Ar⁵.
 22. The compound of claim 1 which is acompound of the formula (Ia)


23. The compound of claim 1 which is a compound of the formula (Ib)


24. The compound of claim 22, where R¹ is a radical of the formulaCHR^(1a)R^(1b), where R^(1a) is selected from the group consisting ofhydrogen and C₁-C₃-alkyl and where R^(1b) is selected from the groupconsisting of C₁-C₄-alkyl; R³ is hydrogen or C₁-C₄-alkyl; R⁴ is C₁-C₄;and R⁵ is hydrogen, fluorine, C₁-C₄-alkoxy or a radical O—Z⁵—Ar⁵. 25.The compound of claim 22, where R¹ is a moiety Z¹—Ar¹; R³ is hydrogen orC₁-C₄-alkyl; R⁴ is C₁-C₄-alkyl; and R⁵ is hydrogen, fluorine orC₁-C₄-alkoxy.
 26. The compound of claim 24, where R²¹ and R²² togetherwith the carbon atom, to which they are bound form a saturated 5- to7-membered carbocyclic ring, which carries a fused benzene ring or afused 5- or 6-membered heteroaromatic ring, where the fused ringsthemselves are unsubstituted or carry 1, 2 or 3 substituents R^(h), andwhere R²³ is hydrogen.
 27. The compound of claim 24, where R²¹ isselected from the group consisting of C₁-C₈-alkyl, trimethylsilyl,C₂-C₈-alkenyl, C₁-C₄-fluoroalkyl, C₃-C₈-cycloalkyl 1, fluorinatedC₃-C₈-cycloalkyl, C₃-C₈-cycloalkyl-C₁-C₄-alkyl, fluorinatedC₃-C₈-cycloalkyl-C₁-C₄-alkyl and Z²—Ar²; R²² is selected from the groupconsisting of hydrogen, fluorine, and C₁-C₈-alkyl; and R²³ is hydrogen.28. The compound of claim 22, where R⁴ is methyl and R⁵ is hydrogen,fluorine or methoxy.
 29. The compound of claim 22, where R⁴ is methyland R⁵ is O—Z⁵—Ar⁵.
 30. The compound of claim 1, which is selected fromthe group consisting of2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopropylmethyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl-phenethyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-methoxy-benzyl)-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-meth oxy-benzyl)-methyl-amide;2-Ethyl-6,7-dimethoxy-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-methoxy-benzyl)-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyli c acidmethyl-(3-trifluoromethyl-benzyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbenzyl-(2-dimethylamino-ethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-benzyl-piperidin-4-yl)-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidtert-butylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidsec-butylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisobutyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopentylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-methyl-butyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1,1-dimethyl-propyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid1,2-dimethyl-propyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2,2-dimethyl-propyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-ethyl-propyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-methyl-butyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidpentylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclohexylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1,3-dimethyl-butyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3,3-dimethyl-butyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-ethyl-butyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbenzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddicyclopropylmethyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-fluoro-ethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclohexylmethyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1-phenyl-ethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-fluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3-fluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid4-fluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2,3-difluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2,4-fluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2,6-difluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3,4-difluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2,2,2-trifluoro-ethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3,5-difluoro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidphenethyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid[1-(4-fluoro-phenyl-ethyl]-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidindan-1-ylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidindan-2-ylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;4-(Azetidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopropylamide;2-Ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin-1-one;2-Ethyl-4-(3-fluoro-pyrrolidine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinolin-1-one;4-(3,3-Difluoro-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;4-(3-Dimethylamino-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one;4-(1,3-Dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;4-(4,4-Difluoro-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisopropylamide;2-Ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one;4-(4-Dimethylamino-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2-H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine-1-carbonyl)-2H-isoquinoline-1-one;4-(4-Cyclopropylmethyl-piperazine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-2H-isoquinolin-1-one;4-[4-(2-Dimethylamino-ethyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-2H-isoquino1-one;4-([1,4′]Bipiperidinyl-1′-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;4-[4-(3-Dimethylamino-propyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidpropylamide;2-Ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl-piperazine-1-carbony-1]-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddimethylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisopropyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddiethylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl-propyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-isopropyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidtert-butyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisobutyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-propyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-dimethylamino-ethyl)-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidethyl-(2-methoxy-ethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopentyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutyl-ethyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidmethyl-pentyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddiisopropylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidisopropyl-propyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclobutylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddipropylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-dimethylamino-propyl)-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclohexyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidcyclopropylmethyl-propyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic aciddiisobutylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbenzyl-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-fluoro-benzyl)-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-fluoro-benzyl)-methyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-fluoro-benzyl)-methyl-amide;2-tert-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide;2-Cyclopropylmethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-(2-Dimethylamino-ethyl)-6,7-dimethoxy-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;6,7-Dimethoxy-1-oxo-2-(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;6,7-Dimethoxy-1-oxo-2-(2-pyrrolidin-1-yl-ethyl)-1,2-isoquinoline-4-carboxylicacid butylamide;2-(2-Fluoro-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide;2-(2,4-Difluoro-benzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Cyclopropyl-6,7-dimethoxy-1-oxo-1-dihydro-isoquinoline-4-carboxylicacid butylamide;6,7-Dimethoxy-1-oxo-2-(2-piperidin-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;6,7-Dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;6,7-Dimethoxy-2-(2-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Isopropyl-6,7-dimethoxy-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide;6,7-Dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide;6,7-Dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;6,7-Dimethoxy-2-(2-methoxy-ethyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acidbutylamide;2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidbutylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide;2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(R)-indan-1-ylamide;2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acidindan-1-ylamide;2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acidbutylamide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(1,2,3,4-tetrahydro-naphthalen-2-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(4-bromo-indan-1-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(5-bromo-indan-1-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid2-dimethylaminomethyl-benzylamide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7-dihydro-5H[1]pyrindin-5-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(6,7-dihydro-5H-[1]pyrindin-7-yl)-amide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid3-dimethylaminomethyl-benzylamide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid4-dimethylaminomethyl-benzylamide;7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid butylamide;7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide;3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid(S)-indan-1-ylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 2-dimethylaminomethyl-benzylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3,5-difluoro-benzylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3,4-difluoro-benzylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid cyclohexylmethyl-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (R)-indan-1-ylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (S)-indan-1-ylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-methoxy-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3-chloro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-dimethylamino-propyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid4-methoxy-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid3-methoxy-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-methoxy-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-methoxy-ethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid4-methyl-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-chloro-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid[(R)-1-(4-fluoro-phenyl)-ethyl]-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-1-(4-fluoro-phenyl)-ethyl]-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(6-methyl-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-morpholin-4-ylmethyl-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(5-chloro-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(6-chloro-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(6-fluoro-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-fluoro-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-methyl-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(5-ethyl-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(6-methoxy-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(5-fluoro-indan-1-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-diethylaminomethyl-benzylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid2-pyrrolidin-1-ylmethyl-benzylamide;2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperidine-1-carbonyl)-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-methoxy-propyl)-amide;4-(3,5-Dimethyl-piperidine-1-carbonyl-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one;2-Ethyl-4-(4-ethyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-one;2-Isobutyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinolin-1-one;2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (2-dimethylamino-ethyl)-amide;2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid butyl-methyl-amide;[(2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonyl)-amino]-aceticacid methyl ester,2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-isopropoxy-propyl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-licacid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (2,3-dihydro-benzofuran-3-yl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide;2-Cyclopropyl-6, 7-dimethoxy-1-oxo-2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide;2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide;2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid indan-1-ylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-piperidine-1-carbonyl)-2H-isoquinolin-1-one;2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine-1-carbonyl)-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(S)indan-1-ylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(R)indan-1-ylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-piperazine-1-carbonyl]-2H-isoquinolin-1-one;2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one;2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one;2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperazine-1-carbonyl]-2H-isoquinolin-1-one;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 2-(morpholine-4-sulfonyl)-benzylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidine-1-carbonyl]-2H-isoquinolin-1-one;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(S)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(R)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide;4-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7-dimethoxy-2H-isoquinolin-1-one;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3-(4-chloro-benzenesulfonylamino)-benzylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (S)-indan-1-ylamide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid 2-(morpholine-4-sulfonyl)-benzylamide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid 3-(4-methoxy-benzenesulfonylamino)-benzylamide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid 3,5-difluoro-benzylamide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid 4-methyl-benzylamide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid cyclohexylmethyl-amide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid butylamide;2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylicacid (2,3-dihydro-benzofuran-3-yl)-amide;2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide;3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid (5,6-dihydro-4-H-cyclopenta[b]thiophen-4-yl)-amide;3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid (2,3-dihydro-benzofuran-3-yl)-amide;3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid indan-1-ylamide;3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin-1-one;or an N-oxide, tautomer, hydrate of pharmaceutically acceptable saltthereof.
 31. The compound of claim 1, which is selected from the groupconsisting of(R)—N-(1-(4-Fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;(S)—N-(1-(4-Fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;N-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl-)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-y-l)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-(4-methylbenzyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;N-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3)-1,2-dihydroisoquinoline-4-carboxamide;N-[(3,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-[(2-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-[[2-(Dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyphenyl)methyl]-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide;N-[(2-tert-Butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-[[(2-(1,1-Dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-[(2,3-Difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-[(3-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-1-oxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline-4-carboxamide;N-[(2,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide;N-[[2-(2-Ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-ox-o-isoquinoline-4-carboxamide;N-[[2-(Cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxy-1-methyl-ethoxy)-4-methyl-phenyl]methyl]-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl-]-1-oxo-isoquinoline-4-carboxamide;N-[[2-(Cyclohexoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-[[2-(Cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3-ylmethoxy)phenyl]-methyl]-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;N-(2-Ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;N-(2-sec-Butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-line-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-1-oxo-N-(2,4,5-trimethylbenzyl)-1,2-dihydroisoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-2-yl)methoxy)benzyl-)-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-1-oxo-N-[[4-(trifluoromethyl)phenyl]methyl]isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-1-oxo-N-[(1S)-1-(p-tolyl)ethyl]isoquinoline-4-carboxamide;2-Ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-1-oxo-N-[(1R)-1-(p-tolyl)ethyl]isoquinoline-4-carboxamide;N-[[4-(Difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-[(4-Cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-carboxamide;N-Indan-1-yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)-ethyl]-1-oxo-isoquinoline-4-carboxamide;N-Butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)-ethyl]-1-oxo-isoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)-ethyl]-1-oxo-isoquinoline-4-carboxamide;N-Butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-carboxamide;N-Indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]-isoquinoline-4-carboxamide;or an N-oxide, tautomer, hydrate or pharmaceutically acceptable saltthereof.
 32. The compound of claim 1 for the use in the treatment of amedical disorder, selected from neurological and psychiatric disorderswhich can be treated by modulation of phosphodiesterase type 10 in amammalian.
 33. The compound of claim 1 for treating, controlling,ameliorating or reducing the risk of CNS disorders in a mammalian. 34.The compound of claim 1 for treating, controlling, ameliorating orreducing the risk of schizophrenia in a mammalian.
 35. The compound ofclaim 1 for treating, controlling, ameliorating or reducing cognitivedysfunction associated with schizophrenia in a mammalian.
 36. Thecompound of claim 1 for treating, controlling, ameliorating or reducingthe risk of bipolar disorders in a mammalian.
 37. The compound of claim1 for treating, controlling, ameliorating or reducing the risk ofdepression in a mammalian.
 38. The compound of claim 1 for treating,controlling, ameliorating or reducing cognitive dysfunction associatedwith Alzheimer's disease in a mammalian.
 39. The compound of claim 1 fortreating, controlling, ameliorating or reducing the risk of diet-inducedobesity in a mammalian.
 40. A method for treating a medical disorder,selected from neurological and psychiatric disorders which can betreated by modulation of phosphodiesterase type 10, said methodcomprising administering an effective amount of at least one compound ofclaim 1 to a subject in need thereof.
 41. A pharmaceutical compositionwhich comprises a carrier and a compound of claim
 1. 42. The compound ofclaim 1 where R¹ is propyl, 1-methyl, n-butyl, 1-methylpropyl,1,1-dimethyl, or 1-ethylpropyl.
 43. The compound of claim 1, where R¹ is1-ethylpropyl.
 44. A compound that is2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid indan-1-ylamide, or a N-oxide thereof, or a tautomer thereof, or ahydrate thereof or a pharmaceutically acceptable salt thereof.
 45. Acompound that is2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydroisoquinoline-4-carboxylicacid butylamide or a N-oxide thereof, or a tautomer thereof, or ahydrate thereof or a pharmaceutically acceptable salt thereof.
 46. Acompound that is2-ethyl-6,7-dimethoxy-N-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamideor a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or apharmaceutically acceptable salt thereof.
 47. A compound that is2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (S)-indan-1-ylamide, or a N-oxide thereof, or a tautomer thereof,or a hydrate thereof or a pharmaceutically acceptable salt thereof. 48.A compound that isN-butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-carboxamideor a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or apharmaceutically acceptable salt thereof.
 49. A compound selected fromthe group consisting of:2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidpyridin-3-ylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(pyrimidin-4-ylmethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-morpholin-4-yl-phenyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(pyridin-4-ylmethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acido-tolylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidm-tolylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-methoxy-phenyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-methoxy-phenyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(pyridin-2-ylmethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidphenylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-fluoro-phenyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(4-methoxy-phenyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidp-tolylamide2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(3-fluoro-phenyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(2-fluoro-phenyl-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acidpyridin-4-ylamide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(tetrahydro-furan-2-ylmethyl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid ([1,3,4]thiadiazol-2-ylmethyl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (thiazol-4-ylmethyl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (thiophen-3-ylmethyl)-amide;2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylicacid (thiazol-2-ylmethyl)-amide;2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid(thiophen-2-ylmethyl)-amide;2-Ethyl-6,7-dimethoxy-N-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-1-oxo-2-(pentan-3-yl-N-(pyridin-3-ylmethyl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-((5-methylthiophen-2-yl)methyl-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;N-((3,5-Dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-N-((3-methylisoxazol-5-yl)methy-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;N-((2,5-Dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-N-((4-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2-yl)methyl)-1,2-dihydroisoquinoline-4-carboxamide;6,7-Dimethoxy-N-((5-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;N-((2-Ethylthiazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-((4-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-((5-methyloxazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)-1,2-dihydro-isoquinoline-4-carboxamide;N-((5-Cyanofuran-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;N-((5-Ethylthiophen-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-((3-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-((2-methylfuran-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydro-isoquinoline-4-carboxamide;6,7-Dimethoxy-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide;2-Ethyl-6,7-dimethoxy-1-oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxamide2-Ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl]-1-oxo-isoquinoline-4-carboxamide;and2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl]-1-oxo-isoquinoline-4-carboxamideor an N-oxide, tautomer, hydrate or pharmaceutically acceptable saltthereof